Mitochondria are heterogeneous and essentially contribute to cellular functions and tissue homeostasis. Mitochondrial dysfunction compromises overall cell functioning, tissue damage, and diseases. The advances in mitochondrion biology increase our understanding of mitochondrial dynamics, bioenergetics, and redox homeostasis, and subsequently, their functions in tissue homeostasis and diseases, including cardiometabolic diseases (CMDs). The functions of mitochondria mainly rely on the enzymes in their matrix. Sirtuins are a family of NAD+-dependent deacylases and ADP-ribosyltransferases. Three members of the Sirtuin family (SIRT3, SIRT4, and SIRT5) are located in the mitochondrion. These mitochondrial Sirtuins regulate energy and redox metabolism as well as mitochondrial dynamics in the mitochondrial matrix and are involved in cardiovascular homeostasis and CMDs. In this review, we discuss the advances in our understanding of mitochondrial Sirtuins in mitochondrion biology and CMDs, including cardiac remodeling, pulmonary artery hypertension, and vascular dysfunction. The potential therapeutic strategies by targetting mitochondrial Sirtuins to improve mitochondrial function in CMDs are also addressed.

Introduction

Cardiometabolic disease (CMD) or cardiometabolic syndrome, remains one of the leading causes of morbidity and mortality worldwide. CMD is a disease entity of maladaptive cardiovascular, renal, metabolic, prothrombotic, and inflammatory abnormalities [1]. The abnormalities in metabolism of the cardiovascular system and other organs contribute to the morbidity and mortality of cardiovascular disease (CVD) individually and interdependently [2,3].

Mitochondria are initially considered as the factories of energy in eukaryotic cells. The roles of mitochondrion go far beyond, besides being the ATP supplier. These cellular organelles regulate multiple cellular processes, including proliferation, immune response, apoptotic cell death, and mediate secondary messenger signals to the nucleus [4]. Mitochondrial dynamics, metabolic regulation, and redox balance co-operate to maintain mitochondrial morphology and function. Increasing lines of evidence in animal models and humans have implicated the central roles of the mitochondrion in tissue metabolism and homeostasis. Mitochondrial damage contributes to the development of CMDs, including heart failure, atherosclerosis, diabetes, and hypertension [58]. Thus, mitochondria have been considered as promising drug targets for improving the outcomes of CMDs [4,5].

The Sirtuins are a family of NAD+-dependent deacylases and ADP-ribosyltransferases. Sirtuins are conserved ranging from yeasts to humans. In mammalian cells, there are seven Sirtuins (from SIRT1 to SIRT7). They are located in the nucleus, cytoplasm, or mitochondrion [9]. Amongst the Sirtuins, SIRT3–5 are located in the mitochondrion, named mitochondrial Sirtuins. The mitochondrial Sirtuins contain an N-terminal mitochondrial signal sequence that dictates translocation of these Sirtuins into mitochondria, where they orchestrate numerous aspects of mitochondrial biology, including redox balance, metabolism homeostasis, and mitochondrial dynamics.

Despite the existence of some functional redundancy, the mitochondrial Sirtuins are still quite different from each other (Table 1). On the one hand, the mitochondrial Sirtuins show distinct enzymatic activities. Although, all the three members show deacetylase activity, the deacetylase activity of SIRT3 is much higher than that of SIRT4 and SIRT5. SIRT3 is the primary determinant of mitochondrial acetyl-proteome [10]. The deacetylase activity is essential for the functions of SIRT3 in mitochondrial biology and pathophysiological processes. SIRT4 is the only ADP-ribosyltransferase in the mitochondria [11]. SIRT4 also shows deacetylase activity and lipoamidase activity [12,13]. Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity [13]. A recent report showed that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine [14]. However, the enzymatic activity of SIRT4 is much lower as compared with the other Sirtuin members [15]. The primary enzymatic activity of SIRT4 has been under debate for a long time. Interestingly, SIRT4 may also function independent of its enzymatic activity under certain conditions [16]. Similar to SIRT4, SIRT5 also displays low deacetylase activity. Instead, SIRT5 is an NAD+-dependent lysine desuccinylase, demalonylase, and deglutarylase [17,18]. SIRT5 serves as a global regulator of lysine succinylation in the mitochondria and targets enzymes in fatty acid oxidation and ketone body production [19]. In addition, SIRT5 is a global regulator of lysine malonylation and provides a mechanism for regulation of energetic flux through glycolysis [20]. On the other hand, the interactome of the mitochondrial Sirtuins is distinguishable. SIRT3 associates with the proteins involved in oxidative balance, fatty acid oxidation, glycolysis, amino acid metabolism, tricarboxylic acid (TCA) cycle, and electron transporter chain (ETC) complexes. Interestingly, the SIRT3 interactome also includes proteins involved in mtDNA replication, transcription, and translation [21]. By contrast, SIRT4 and SIRT5 interact with relatively fewer proteins. Enriched SIRT4 reactome pathways include oxidative balance, fatty acid metabolism, glycolysis, amino acid catabolism, and biotin transport and metabolism [13,21]. Although some of the SIRT4-interacting proteins have been identified by proteomics, few of them have been validated in physiological or pathological processes. SIRT5 is considered the global regulator of lysine succinylation and malonylation, but very few proteins interact with SIRT5 [21]. The difference in primary enzymatic activity and interactomes determines the distinguishable functions of different Sirtuins.

Table 1
Enzymatic activity and substrates of mitochondrial Sirtuins
Molecular weightEnzymatic activityValidated targets in individual processes of mitochondrionReferences
SIRT3 43 kDa 28 kDa Deacetylase • Oxidative stress (MnSOD) [24
   • Fatty acid metabolism (LCAD)  [32
   • Pyruvate metabolism (PDH complex)  [36,37
   • Ketone body metabolism (HMGCS2)  [43
   • Glutamine metabolism (GDH, GOT2)  [48,144
   • TCA cycle (SDHA, IDH2, AceCS2)  [25,50,145
   • Oxidative phosphorylation (ATP synthase β, NDUFA9, ATP5O)  [21
   • Mitochondrial dynamics (cyclophilin D, OPA1)  [53,62
   • Mitochondrial transcription and translation (LRP130, MRPL10)  [21
   • Urea cycle (OTC)  [150]  
SIRT4 35 kDa Deacetylase • Fatty acid metabolism (MCD, ECHA) [12,34
  ADP-ribosyltransferase • Glutamine metabolism (GDH) [11
  Lipoamidase • Pyruvate metabolism (DLAT) [13
  Deacylase • Branched-chain amino acid metabolism (MCCC) [14
SIRT5 34 kDa Deacetylase • Urea cycle (CPS1, UOX) [146,147
  Demalonylase • Glycolysis (GAPDH) [20
  Desuccinylase • Oxidative stress (CuZnSOD) [17
   • Fatty acid metabolism (ECHA)  [33
   • Glutamine metabolism (GLS)  [47
   • Ketone body metabolism (HMGCS2)  [19
   • TCA cycle (SDH, IDH2)  [29,30
   • Urea cycle (CPS1)  [47
  Deglutarylase • Urea cycle (CPS1) [148
Molecular weightEnzymatic activityValidated targets in individual processes of mitochondrionReferences
SIRT3 43 kDa 28 kDa Deacetylase • Oxidative stress (MnSOD) [24
   • Fatty acid metabolism (LCAD)  [32
   • Pyruvate metabolism (PDH complex)  [36,37
   • Ketone body metabolism (HMGCS2)  [43
   • Glutamine metabolism (GDH, GOT2)  [48,144
   • TCA cycle (SDHA, IDH2, AceCS2)  [25,50,145
   • Oxidative phosphorylation (ATP synthase β, NDUFA9, ATP5O)  [21
   • Mitochondrial dynamics (cyclophilin D, OPA1)  [53,62
   • Mitochondrial transcription and translation (LRP130, MRPL10)  [21
   • Urea cycle (OTC)  [150]  
SIRT4 35 kDa Deacetylase • Fatty acid metabolism (MCD, ECHA) [12,34
  ADP-ribosyltransferase • Glutamine metabolism (GDH) [11
  Lipoamidase • Pyruvate metabolism (DLAT) [13
  Deacylase • Branched-chain amino acid metabolism (MCCC) [14
SIRT5 34 kDa Deacetylase • Urea cycle (CPS1, UOX) [146,147
  Demalonylase • Glycolysis (GAPDH) [20
  Desuccinylase • Oxidative stress (CuZnSOD) [17
   • Fatty acid metabolism (ECHA)  [33
   • Glutamine metabolism (GLS)  [47
   • Ketone body metabolism (HMGCS2)  [19
   • TCA cycle (SDH, IDH2)  [29,30
   • Urea cycle (CPS1)  [47
  Deglutarylase • Urea cycle (CPS1) [148

Abbreviations: AceCS2, acetyl-CoA synthetase 2; CPS1, carbamoyl-phosphate synthase 1; CuZnSOD, copper- and zinc-containing superoxide dismutase; DLAT, dihydrolipoyllysine acetyltransferase; ECHA, enoyl-CoA hydratase α-subunit; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GDH, glutamate dehydrogenase; GLS, glutaminase; GOT2, glutamate oxaloacetate transaminase 2; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; IDH2, isocitrate dehydrogenase 2; LCAD, long-chain acyl-CoA dehydrogenase; MCCC, methylcrotonoyl-CoA carboxylase complex; MCD, malonyl-CoA decarboxylase; MnSOD, manganese-dependent superoxide dismutase; OCT, ornithine transcarbamylase; OPA1, optic atrophy 1; SDH, succinate dehydrogenase; TCA, tricarboxylic acid.

A growing body of evidence suggests that the mitochondrial Sirtuins participate in the pathophysiology of CMDs (Table 2). Here, in this review, we will discuss the current advances in our understanding of the functions of the mitochondrial Sirtuins in mitochondrion biology and CMDs, including cardiac remodeling, pulmonary artery hypertension, and vascular dysfunction. We will also address the potential therapeutic applications and raise important questions that are elusive.

Table 2
Cardiac and vascular phenotypes in mice with mitochondrial Sirtuins knockout and transgene
GenotypeCardiac phenotypeReferences
Sirt3-KO Sirt3-KO mice develop hypertrophy, fibrosis, and contractile dysfunction with age [22
 Sirt3-KO mice are highly susceptible to stress-induced cardiac hypertrophy  [22,58
 Sirt3-KO mice are more sensitive to doxorubicin-induced cardiotoxicity  [53
 Sirt3-KO mice are more susceptible to ischemic injury  [71]  
 Sirt3-KO mice are more sensitive to cardiac dysfunction induced by obesity and diabetes  [86,87,91]  
SIRT3-Tg SIRT3 overexpression protects the heart from stress and ageing-induced cardiac remodeling [22,149
Sirt4-KO Sirt4-KO mice have no basal cardiac abnormalities but less susceptible to cardiac hypertrophic stimuli [16
SIRT4-Tg • Mice with cardiac-specific SIRT4 overexpression are highly susceptible to cardiac hypertrophic stimuli [16
Sirt5-KO Sirt5 deficiency causes hypertrophic cardiomyopathy [33
 Sirt5-KO mice are more sensitive to ischemic injury  [30]  
Genotype Vascular phenotype References 
Sirt3-KO Sirt3-KO mice develop spontaneous pulmonary arterial hypertension [40,73
 Sirt3-KO reduces angiogenic capacity of endothelial cells and vasorelaxation  [105]  
 Sirt3 deficiency does not affect the sensitivity to atherosclerosis  [115
Sirt4-KO Sirt4 deficiency does not affect basal and Ang II-induced increase in blood pressure [16
GenotypeCardiac phenotypeReferences
Sirt3-KO Sirt3-KO mice develop hypertrophy, fibrosis, and contractile dysfunction with age [22
 Sirt3-KO mice are highly susceptible to stress-induced cardiac hypertrophy  [22,58
 Sirt3-KO mice are more sensitive to doxorubicin-induced cardiotoxicity  [53
 Sirt3-KO mice are more susceptible to ischemic injury  [71]  
 Sirt3-KO mice are more sensitive to cardiac dysfunction induced by obesity and diabetes  [86,87,91]  
SIRT3-Tg SIRT3 overexpression protects the heart from stress and ageing-induced cardiac remodeling [22,149
Sirt4-KO Sirt4-KO mice have no basal cardiac abnormalities but less susceptible to cardiac hypertrophic stimuli [16
SIRT4-Tg • Mice with cardiac-specific SIRT4 overexpression are highly susceptible to cardiac hypertrophic stimuli [16
Sirt5-KO Sirt5 deficiency causes hypertrophic cardiomyopathy [33
 Sirt5-KO mice are more sensitive to ischemic injury  [30]  
Genotype Vascular phenotype References 
Sirt3-KO Sirt3-KO mice develop spontaneous pulmonary arterial hypertension [40,73
 Sirt3-KO reduces angiogenic capacity of endothelial cells and vasorelaxation  [105]  
 Sirt3 deficiency does not affect the sensitivity to atherosclerosis  [115
Sirt4-KO Sirt4 deficiency does not affect basal and Ang II-induced increase in blood pressure [16

Abbreviations: Ang II, angiotensin II

Mitochondrial sirtuins in oxidative stress, metabolism, and dynamics

Mitochondrial Sirtuins regulate oxidative stress

Oxidative stress is a central mechanism underlying stress- and ageing-induced CMDs [7]. All mitochondrial Sirtuins have been implicated in redox homeostasis in the mitochondrion directly or indirectly (Figure 1).

Landscape of mitochondrial Sirtuins in mitochondrial biology

Figure 1
Landscape of mitochondrial Sirtuins in mitochondrial biology

Primary metabolic, redox, and dynamic pathways in the mitochondria and the different roles mitochondrial Sirtuins play in those pathways. Green arrows indicate activating effects; red bars denote inhibiting functions; and blue arrows indicate metabolic flux. Abbreviations: AceCS2, acetyl-CoA synthetase 2; CPS1, carbamoyl-phosphate synthase 1; CuZnSOD, copper- and zinc-containing superoxide dismutase; CypD, cyclophilin D; ECHA, enoyl-CoA hydratase, α subunit; GDH, glutamate dehydrogenase; GLS, glutaminase; GOT2, glutamate oxaloacetate transaminase 2; HADHA, hydroxyacyl-CoA dehydrogenase, α subunit; IDH2, isocitrate dehydrogenase 2; LCAD, long-chain acyl-CoA dehydrogenase; MCCC, methylcrotonoyl-CoA carboxylase complex; MCD, malonyl-CoA decarboxylase; MnSOD, manganese-dependent superoxide dismutase; OTC, ornithine transcarbamylase; OPA1, optic atrophy 1; PDC, pyruvate dehydrogenase complex; SDH, succinate dehydrogenase; VDAC, voltage-dependent anion channel.

Figure 1
Landscape of mitochondrial Sirtuins in mitochondrial biology

Primary metabolic, redox, and dynamic pathways in the mitochondria and the different roles mitochondrial Sirtuins play in those pathways. Green arrows indicate activating effects; red bars denote inhibiting functions; and blue arrows indicate metabolic flux. Abbreviations: AceCS2, acetyl-CoA synthetase 2; CPS1, carbamoyl-phosphate synthase 1; CuZnSOD, copper- and zinc-containing superoxide dismutase; CypD, cyclophilin D; ECHA, enoyl-CoA hydratase, α subunit; GDH, glutamate dehydrogenase; GLS, glutaminase; GOT2, glutamate oxaloacetate transaminase 2; HADHA, hydroxyacyl-CoA dehydrogenase, α subunit; IDH2, isocitrate dehydrogenase 2; LCAD, long-chain acyl-CoA dehydrogenase; MCCC, methylcrotonoyl-CoA carboxylase complex; MCD, malonyl-CoA decarboxylase; MnSOD, manganese-dependent superoxide dismutase; OTC, ornithine transcarbamylase; OPA1, optic atrophy 1; PDC, pyruvate dehydrogenase complex; SDH, succinate dehydrogenase; VDAC, voltage-dependent anion channel.

SIRT3 can repress oxidative stress in cytoplasm and mitochondrion. In the cytoplasm, SIRT3 binds to the transcriptional factor FoxO3a and deacetylates it. Deacetylated FoxO3a translocates into the nucleus and subsequently increases the expression of the antioxidants manganese-dependent superoxide dismutase (MnSOD) and catalase, which converts superoxide (O2) into H2O2 and inhibits oxidative stress [22]. Interestingly, FoxO3a is also located in the mitochondrion, where SIRT3 could deacetylate it directly and promote its translocation into the cytoplasm and nucleus to trigger the expression of downstream antioxidants [23]. In the mitochondrion, SIRT3 deacetylates MnSOD directly. SIRT3-mediated hypoacetylation of MnSOD increases its activity to reduce the oxidative stress [24]. SIRT3 also controls reactive oxygen species (ROS) through an indirect manner by promoting the TCA cycle and ETC efficiency. SIRT3 promotes glutathione production by directly deacetylating and activating isocitrate dehydrogenase (IDH2), a key enzyme within the TCA cycle, increasing NADPH levels and the ratio of reduced-to-oxidized glutathione. Overexpression of SIRT3 increases NADPH levels and protects cells from oxidative stress-induced damage [25]. In addition, SIRT3 deacetylates all ETC complexes to promote efficient electron transport, resulting in reduced ROS production and maximizing ATP generation [26].

In addition to SIRT3, SIRT5 also shows antioxidative capacity. SIRT5 regulates oxidative stress response in cardiomyocytes [27]. Copper- and zinc-containing superoxide dismutase (CuZnSOD), a key antioxidant enzyme converts superoxide into H2O2 in cytoplasm or mitochondria. SIRT5 desuccinylates and activates CuZnSOD, leading to a reduction in cellular ROS level [28]. What is more, SIRT5 desuccinylates IDH2 and deglutarylates glucose-6-phosphate dehydrogenase (G6PD), respectively, activating both NADPH-producing enzymes to maintain redox homeostasis [29]. SIRT5 also indirectly represses mitochondrial oxidative stress by regulating the activity of succinate dehydrogenase (SDH), a key enzyme in the TCA cycle and ETC [30].

Different from SIRT3 and SIRT5, SIRT4 acts as an enzyme promoting the ROS generation during stress. Our recent work shows that SIRT4 elevates mitochondrial ROS by inhibiting SIRT3-mediated deacetylation of MnSOD. SIRT4-mediated inhibition of MnSOD facilitates angiotensin II (Ang II)-induced production of mitochondrial ROS [16]. Another current work also identifies various oxidation-related enzymes that could interact with SIRT4 [13], indicating that SIRT4 may also regulate these oxidation-related enzymes directly. The effects of SIRT4 on oxidative stress is also validated in another study [31]. However, the specific targets of SIRT4 in regulating mitochondrial oxidative stress remain to be identified.

Taken together, the mitochondrial SIRT3 and SIRT5 act as antioxidants whereas SIRT4 promotes the generation of mitochondrial ROS.

Mitochondrial Sirtuins regulate metabolic processes

The mitochondrial Sirtuins participate in nearly all the aspects of mitochondrial metabolism (Figure 1). Here, we discuss the primary metabolic processes that are involved in CMDs.

Fatty acid oxidation

The roles of the mitochondrial Sirtuins in fatty acid oxidation are widely investigated. SIRT3 promotes fatty acid oxidation by deacetylating the enzymes, such as long-chain acyl-CoA dehydrogenase (LCAD). LCAD is hyperacetylated at Lys42 in the absence of SIRT3. During fasting, LCAD is deacetylated in liver by SIRT3, which increases its enzymatic activity. Compared with wild-type mice, the Sirt3-KO mice exhibit hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure [32]. SIRT3 also targets other enzymes involved in fatty acid oxidation, including medium chain-specific acyl-CoA dehydrogenase (ACADM) and acylglycerol kinase (AGK) [21]. In addition to SIRT3, SIRT5 promotes the efficiency of fatty acid oxidation. SIRT5 targets enoyl-CoA hydratase α-subunit (ECHA), also known as hydroxyacyl-CoA dehydrogenase α subunit (HADHA). ECHA is involved in fatty acid oxidation and catabolism of branched-chain amino acids (BCAAs). SIRT5 desuccinylates ECHA and increases the activity of ECHA, promoting the oxidation of long chain acyl-CoAs and increasing ATP production [33]. By contrast, SIRT4 acts as an inhibitor for fatty acid oxidation. SIRT4 deacetylates ECHA and inhibits its activity to repress fatty acid oxidation [34]. SIRT4 also deacetylates and inhibits malonyl CoA decarboxylase (MCD), which is an enzyme that produces acetyl CoA from malonyl CoA. SIRT4 is active in nutrient repletion conditions and deacetylates MCD to repress fatty acid oxidation while promoting lipid anabolism [12]. Indirectly, SIRT4 also controls peroxisome proliferator activated receptor α (PPARα) to inhibit genes associated with fatty acid catabolism [35].

Glucose metabolism

As the mitochondrial Sirtuins localize in the mitochondrial matrix, they control the last step of glycolysis, namely the conversion of pyruvate to acetyl-CoA, by regulating the pyruvate dehydrogenase complex (PDC). Pyruvate dehydrogenase E1α (PDHA1) is the first component enzyme of the PDC. SIRT3 deacetylates PDHA1 and elevates its activity [36,37]. SIRT3 deacetylates and enhances the activity of the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis and supplying pyruvate in the mitochondria [38]. SIRT3 also controls glycolysis in an indirect way. SIRT3 loss increases ROS production, leading to stabilization of hypoxia inducible factor-1α (HIF1α), a transcription factor that regulates glycolytic gene expression [39,40]. Differently, SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), leading to a reduction in PDC activity [13]. SIRT5-mediated lysine desuccinylation represses the activity of PDC [18]. SIRT5 is also a global regulator of lysine malonylation and provides a mechanism for regulation of energetic flux through glycolysis. Malonylation suppresses the activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). In primary hepatocytes of Sirt5-KO mice, the glycolytic flux was diminished compared with that of the WT mice [20].

Ketone body metabolism

The failing heart relies on ketone bodies as a fuel in rodents and humans [41,42]. 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting step in the β-hydroxybutyrate synthesis. In response to fasting, SIRT3 deacetylates HMGCS2, leading to increase in HMGCS2 activity. Mice lacking SIRT3 show decreased β-hydroxybutyrate levels during fasting [43]. Ketone body synthesis is also highly targetted by SIRT5. SIRT5 regulates succinylation of HMGCS2, and Sirt5 knockout reduces the level of β-hydroxybutyrate in the liver during fasting [19]. These facts support the notion that mitochondrial Sirtuins participate in the synthesis and utilization of ketones, which may contribute to their roles in CVDs.

Amino acid catabolism

Defects in BCAAs catabolism are critically associated with heart failure and ischemic injury [44,45]. All the mitochondrial Sirtuins are reported to interact with enzymes involved in BCAAs catabolism [10,14,33]. Nearly half of the proteins involved in BCAA catabolism pathway contain significantly increasing acetyl sites in Sirt3-KO livers [10]. SIRT4 ablation reduces leucine and BCAA metabolic flux. Sirt4-KO mice show increased leucine-stimulated insulin secretion through regulation of methylcrotonyl-CoA carboxylase complex (MCCC) [14]. As described above, SIRT4 and SIRT5 regulate the activity of ECHA, which is also an enzyme for BCAA catabolism [33,34]. Glutamine level is associated with CVDs [46]. Mitochondrial Sirtuins also regulate glutamine metabolism. Glutamine is converted into glutamate by glutaminase (GLS), which can be activated by SIRT5-meditated desuccinylation [47]. Glutamate dehydrogenase (GDH) catalyzes the reversible NADP+-linked oxidative deamination of glutamate into α-ketoglutarate, which enters the TCA cycle. SIRT3 deacetylates and activates GDH, whereas SIRT4 mediates the ADP-ribosylation of GDH and inhibits the activation of GDH [11,48]. Therefore, the mitochondrial Sirtuins may also regulate the BCAA and glutamine catabolism in cardiovascular tissues.

TCA cycle and ETC

The TCA cycle and ETC couple redox balance and ATP generation [49]. All the members of mitochondrial Sirtuins can regulate the TCA cycle. SIRT3 deacetylates the TCA cycle enzyme IDH2, and promotes the oxidation of isocitrate into α-ketoglutarate, thus producing NADPH [25]. SIRT3 also deacetylates the SDH (or ETC complex II) to activate it [50]. SIRT4 also interacts with some components of the TCA cycle [21]. However, whether it regulates the activity of TCA cycle remains unknown. IDH2 and SDH can also be targetted by SIRT5-mediated desuccinylation [29]. However, SIRT5 activates IDH2 but inhibits SDH [18,29]. Mitochondrial Sirtuins also regulate the electron transfer process. SIRT3 controls the activity of the mitochondrial complexes I–V and the ATP synthase [21]. SIRT4 and SIRT5 also interact with the complexes of the electron transfer chain [21], however, their specific targets and effects on electron transfer chain are yet to be identified.

Mitochondrial Sirtuins regulate the dynamics of mitochondria

Mitochondria are highly dynamic organelles that constantly fuse and divide in response to cell demands and the environment. The dynamics of mitochondria are also regulated by the mitochondrial Sirtuins (Figure 1).

Perturbation in mitochondrial dynamics is responsible for mitochondrial dysfunction, which underlies various human diseases, including CMDs [8]. Proteolytic processing of the dynamin-like GTPase optic atrophy 1 (OPA1) in the inner membrane of mitochondria is a critical regulatory step to balance mitochondrial fusion and fission [51]. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice [52]. SIRT3 is capable of deacetylating OPA1 and elevating its GTPase activity [53]. SIRT3 also maintains the protein level of OPA1 upon stress such as in acute kidney injury [54]. Loss of SIRT3 leads to the increase in the levels of mitochondrial fission factor (MFF) and recruitment of dynamin-related protein 1 (DRP1) on the mitochondrial outer membrane, which is accompanied by a decrease in the OPA1 protein [54]. This effect carries mitochondrial dynamics toward fission and fragmentation and sustains mitochondrial depolarization, resulting in accumulation of PTEN-induced putative kinase 1 (PINK1) in the organelles and activation of mitophagy [54]. DRP1 is also regulated by SIRT4. SIRT4 inhibits both DRP1 phosphorylation and DRP1 recruitment to the mitochondrial membrane via an interaction with mitochondrial fission protein 1 (FIS1) [55]. Sirt4-knockout causes mitochondrion enlargement and decreases the number of mitochondria in the periportal zone of the liver in mice [35]. However, the mechanism by which SIRT4 represses DRP1–FIS1 interaction remains unknown. SIRT5 is essential for starvation-induced mitochondrial elongation. Sirt5 deficiency in mouse embryonic fibroblasts increases the levels of mitochondrial dynamics in 51-kDa protein (MID51) and FIS1, leading to mitochondrial accumulation of the profission DRP1 and mitochondrial fragmentation. Sirt5 deletion reduces mitochondrial elongation, leading to increased mitophagy during starvation or ammonia-induced stress [47,56]. However, this effect of SIRT5 seems to be a result of deregulation of glutamine metabolism [47], whether SIRT5 directly regulates mitochondrial dynamics remains to be elucidated.

Mitochondrial Sirtuins in CMDs

Mitochondrial Sirtuins are important mediators of redox homeostasis, metabolic plasticity, and mitochondrial dynamics. These roles of mitochondrial Sirtuins in response to stress are fundamental for the development of CMDs. Notably, mice with the deficiency of mitochondrial Sirtuins do not show any obvious health issues under normal physiological conditions in most studies. For instance, Sirt3-knockout mice are unremarkable in metabolism and redox under normal physiological conditions [25,32,48,57]. Instead, mitochondrial Sirtuins are important regulators of the adaption to stress, including obesity, diabetes, toxic drugs, fasting, and caloric restriction (CR). Here, we discuss the emerging roles of mitochondrial Sirtuins in CMDs, including cardiac hypertrophy, ischemia injury, drug-induced cardiotoxicity, cardiac lipotoxicity and diabetic cardiomyopathy, pulmonary artery hypertension, and endothelial dysfunction.

Cardiac hypertrophy

All the three members of mitochondrial Sirtuins participate in cardiac homeostasis. The roles of SIRT3 in the hypertrophic growth of the heart are widely investigated. SIRT3 is dynamically regulated by hypertrophic stress [22,58]. The effect on oxidative stress is one of the major contributors to the functions of SIRT3 in cardiac hypertrophy. For instance, SIRT3-mediated reduction in ROS suppresses Ras activation and downstream signaling through the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways. This effect leads to the repression of the activity of transcription factors, specifically GATA-binding protein 4 (GATA4) and nuclear factor of activated T cells (NFAT), and translation factors, specifically eukaryotic initiation factor 4E (eIf4E) and S6 ribosomal protein (S6P). These transcription and translation factors are critically involved in the development of cardiac hypertrophy induced by various stresses such as Ang II, isoproterenol infusion, or transverse aortic constriction (TAC) [22]. Four weeks following TAC, Sirt3-KO mice show decreased ejection fraction compared with WT mice, accompanied by a greater degree of cardiac hypertrophy and fibrosis [58,59]. The decline in cardiac function in Sirt3-KO mice is also accompanied by the defects in palmitate oxidation, glucose oxidation, oxygen consumption, and increased glycolysis [59]. Additionally, Sirt3-KO mice show reduced respiratory capacity and ATP synthesis in cardiac mitochondria [59]. What is more, abnormal lipid accumulation is also observed in the hypertrophic hearts of Sirt3-KO mice [60]. Interestingly, SIRT3 regulates mitochondrial NAD+ homeostasis by physically interacting with and deacetylating the mitochondrial NMN adenylyltransferase 3 (NMNAT3). NMNAT3 is a central enzyme in NAD+ biosynthesis that catalyzes the condensation of NMN to form NAD+. In turn, NMNAT3 contributes to SIRT3-mediated antihypertrophic effects in cardiomyocytes by supplying NAD+ in the mitochondrion [61]. Loss of SIRT3 also causes age-dependent cardiac hypertrophy, partially by regulating the opening of mitochondrial permeability transition pore (mPTP) via deacetylating the regulatory component of the mPTP, cyclophilin D (CypD) [62].

Interestingly, SIRT4 is the only Sirtuin member showing prohypertrophic function in the heart. In Ang II-induced hypertrophic hearts, SIRT4 inhibits MnSOD activity and promotes the accumulation of ROS, which leads to the activation of MAPK/ERK pathway and aggravates cardiac hypertrophy [16]. Inhibition of ROS with MnTBAP, a synthetic metalloporphyrin, represses SIRT4-mediated promotion of cardiac hypertrophy [16]. Interestingly, the effects of SIRT4 are independent of its enzymatic activity [16]. SIRT4 binds to SIRT3, which inhibits SIRT3-mediated deacetylation and activation of MnSOD. Overexpression of an enzymatic mutant of SIRT4 (SIRT4H161Y) also inhibits MnSOD–SIRT3 interaction, thus repressing SIRT3-mediated deacetylation of MnSOD. Likewise, SIRT4H161Y also inhibits MnSOD activity and elevates mitochondrial ROS in cardiomyocytes upon Ang II treatment. In fact, the Sirtuin family and histone deacetylases (HDACs) can function in an indirect manner. Some examples are SIRT1 [6365], SIRT6 [66,67], SIRT7 [68], and HDAC1 [69]. For instance, it was reported that SIRT1-mediated neuroprotection is independent of its deacetylase activity [65]. In addition, SIRT6 suppresses cancer stem-like capacity in tumors with PI3K activation independent of its deacetylase activity [67]. Despite these individual reports, it is largely unknown that in which diseases the enzymatic activity matters and in which diseases the nonenzymatic activity plays the major role. In this regard, further biochemical and physiological investigations are urgently needed for Sirtuin biology to study their enzyme-dependent and -independent functions.

Similar to SIRT3, SIRT5 also exhibits cardioprotective function. Sirt5 deficiency causes hypertrophic cardiomyopathy in mice. SIRT5 regulates metabolism to repress cardiac hypertrophy. In the mitochondrion, more than 100 succinylated proteins are potentially regulated by SIRT5. These proteins participate in metabolic processes such as fatty acid β-oxidation and BCAA catabolism, and the respiratory chain [30,33]. In mice hearts, Sirt5 deficiency reduces ECHA activity and leads to accumulation of long-chain CoAs and decline in cardiac ATP levels. As a consequence, Sirt5-knockout mice develop hypertrophic cardiomyopathy as early as 8-weeks old [33]. The antihypertrophic function of SIRT5 may also depend upon the antioxidative role of SIRT5 [29,33].

Cardiac ischemia injury

Mitochondria play an important role in cell death, cardioprotection, and function recovery during ischemic injury [70]. Mitochondrial ROS is an important contributor to ischemic injury in the heart. Mitochondrial Sirtuins are reported to participate in myocardial ischemia. Indeed, Sirt3 down-regulation increases adult mice hearts to ischemia–reperfusion (IR) injury and contributes to a greater level of IR injury in the aged heart [71]. Remarkedly, Sirt3 knockout leads to coronary microvascular dysfunction and preserves recovery of cardiac function following IR [72,73]. Loss of Sirt3 in bone marrow cells (BMC) limits BMC-mediated angiogenesis and cardiac repair in post-myocardial infarction [74]. Additionally, in patients with myocardial ischemia, total 23 DNA sequence variants (DSVs) at SIRT3 promoter are identified [75]. These DSVs may change the SIRT3 level by affecting the transcription of SIRT3 gene and contribute to the development of myocardial ischemia. Taken together, SIRT3 is essential for preventing ischemic injury and contributes to the recovery of cardiac function. Effects on redox may be the primary mechanism underlying SIRT3 function.

Loss of Sirt5 increases IR injury, which depends on the effects of SIRT5 on SDH activity [30]. SDH is the only enzyme that participates in both the TCA cycle and the ETC, which makes SDH a core regulatory factor of metabolic and redox homeostases. Ischemic accumulation of succinate controls reperfusion injury through mitochondrial ROS [76]. Indeed, Sirt5 knockout induces metabolic defects in the heart [33], and increased mitochondrial ROS level during myocardial ischemia [30]. SIRT5 also protects the brain from ischemic injury by maintaining mitochondrial respiration [77]. Therefore, controlling metabolism and mitochondrial ROS by targetting SIRT5 may be a promising strategy for treatment of myocardial ischemia. Taken together, mitochondrial Sirtuins essentially participate in myocardial ischemia, but the underlying mechanisms are not entirely understood.

Drug-induced cardiotoxicity

Drug-induced cardiotoxicity is common in the clinic. The cardiotoxicity of certain chemotherapeutic agents has led to the emergence of cardio-oncology [78]. One such drug is doxorubicin. Doxorubicin is an anthracycline drug used for the treatment of leukemia in children, but it induces cardiotoxicity in some patients [79]. Mitochondrial dysfunction is an important mechanism underlying doxorubicin-induced cardiotoxicity [80]. Mitochondrial Sirtuins inhibit doxorubicin-induced damage through repression of oxidative stress and improvement of mitochondrial dynamics. Doxorubicin reduces the SIRT3 level and increases the lysine acetylation of mitochondrial proteins. SIRT3 overexpression attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in cardiomyocytes [81]. In mouse, Sirt3 knockout promotes mtDNA damage, ROS production, and the development of doxorubicin-induced cardiomyopathy, whereas SIRT3 overexpression improves mitochondrial function and protects the heart from doxorubicin-induced cardiotoxicity [82]. SIRT3 promotes mitochondrial function not only by regulating the activity of antioxidative enzymes but also by regulating mitochondrial dynamics during doxorubicin-induced damage [53,82]. Proteolytic processing of the dynamin-like GTPase OPA1 in the inner membrane of mitochondria is a critical regulatory step to balance mitochondrial fusion and fission [51]. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mouse [52]. SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics and protects cardiomyocytes from doxorubicin-induced mitochondrial destruction and cell death [53]. Similarly, Sirt3 knockout exacerbates cadmium-induced hepatotoxicity and gentamicin-induced ototoxicity by increasing mitochondrial ROS and autophagic cell death [83,84]. Therefore, SIRT3-mediated antioxidative effects and structural and functional integrity of mitochondrion may be a common mechanism underlying its function in preventing drug-induced toxicity in different tissues. Further works elucidating the potential participation of SIRT4 and SIRT5 in drug-induced cardiotoxicity would also be interesting.

Cardiac lipotoxicity and diabetic cardiomyopathy

Obesity and diabetes are the two important contributors to cardiac metabolic diseases. Cardiac lipotoxicity is common in patients with obesity. Mitochondrial Sirtuins are involved in obesity. SIRT3 and SIRT4 are reported to repress and promote high-fat diet (HFD) induced obesity [12,85]. These facts implicate that mitochondrial Sirtuins may be involved in obesity-related cardiac lipotoxicity. The expression of SIRT3 is reduced in the heart from mice fed on HFD [86,87]. SIRT3 plays an important role in preserving heart function in the setting of obesity. HFD induces features of cardiac lipotoxicity, including fatty acid accumulation, deregulation of fatty acid oxidation, elevated oxidative stress, cardiac remodeling, and dysfunction. Cardiac lipotoxicity is exacerbated in the hearts of Sirt3-knockout mice [59,86,87]. This effect is concomitant with increased acetylation of mitochondrial β-oxidation enzymes, such as β-HAD and LCAD, implicating that metabolism may be the primary mechanism underlying SIRT3 function in lipotoxicity [59,60,86,87]. Mitochondrial Sirtuins also participate in insulin resistance and diabetes [11,85,88]. SIRT3 prevents diabetes-induced damage in diverse tissues, including skeletal muscle [89], retina [90], and heart [91,92]. In streptozotocin-induced diabetes, Sirt3 deficiency exacerbates cardiac dysfunction through decrease in Foxo3a-Parkin-mediated mitophagy [91]. Furthermore, SIRT3 is also essential for apelin-induced cardiac angiogenesis in post-myocardial infarction of diabetes [92]. Oxidative stress is a fundamental mechanism underlying lipotoxicity and diabetic cardiomyopathy [93,94]. To this context, SIRT3 may also regulate oxidative stress to inhibit cardiac lipotoxicity and diabetic cardiomyopathy. Collectively, these facts suggest that SIRT3 inhibits cardiomyopathy concomitant with obesity and diabetes. However, the roles of SIRT4 and SIRT5 in obesity-related cardiac lipotoxicity and diabetic cardiomyopathy remain to be elucidated.

Pulmonary remodeling and hypertension

Pulmonary arterial hypertension (PAH) is caused by excessive proliferation of vascular cells such as smooth muscle cells and endothelial cells (ECs) that eventually obliterate the pulmonary arterial lumen. PAH can lead to right ventricular failure and premature death. Abnormal mitochondria in pulmonary arteries contribute to pulmonary remodeling and hypertension [4,95]. The role of SIRT3 in the pulmonary vascular system is well documented. Waypa et al. [96] first showed that Sirt3-KO mice (C57BL/6 background) housed in chronic hypoxia developed PAH that was indistinguishable from wild-type littermates. Interestingly, a later work by Paulin et al. [40] demonstrated that SIRT3 prevented PAH in rodents and humans. The authors provided evidence that Sirt3-knockout mice (129/Sv background) developed spontaneous PAH, with a decline in the function of the right ventricle. This phenotype is partially due to the down-regulation of glucose oxidation and up-regulation of glycolysis. This shift of metabolism leads to HIF-1α stabilization, signal transducer and activator of transcription 3 (STAT3) and NFATc2 activation, which are key contributors to the development of PAH [40]. Importantly, the latter work also provided substantial evidence that the SIRT3 loss-of-function polymorphism rs11246020 was associated with human idiopathic PAH [40]. Different genetic backgrounds may partially explain the conflict in mouse models between these two studies. 129/Sv mice are more sensitive to CVDs than C57BL/6 mice [97]. The effects of SIRT3 on pulmonary remodeling are also validated by further reports. For instance, Lai et al. [98] reported that SIRT3–AMPK activation in the skeletal muscle contributed to nitrite/metformin-mediated protection of pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) in rat and mouse models [98]. In addition, SIRT3 also regulates fibroblast-myofibroblast differentiation by deacetylating and inactivating glycogen synthase kinase 3 β (GSK3β). As a result, SIRT3 significantly delays the ageing-related or bleomycin-induced pathophysiology of pulmonary fibrosis in 129/Sv or C57BL/6 mice [99,100]. Collectively, the evidence from mouse, rat, and human patients is sufficient to support the notion that SIRT3 in vascular smooth muscle cells and fibroblasts is dramatically associated with pulmonary remodeling and hypertension. SIRT4 and SIRT5 regulate metabolism and redox homeostasis in lung epithelial cells and modulate the development of lung cancer [101103], indicating that these two members may also participate in pulmonary remodeling.

Endothelial dysfunction

Endothelial dysfunction is involved in nearly all the CVDs. Although ECs only have a low content of mitochondrion, the mitochondrion is still a key factor for EC homeostasis. Damage to mitochondrial homeostasis contributes to endothelial dysfunction and subsequent vascular diseases [4].

Amongst the mitochondrial Sirtuins, SIRT3 is well investigated in vascular ECs. Deregulation of SIRT3 is observed in the ECs from diabetic and obese patients. In diabetic patients, loss of SIRT3 is associated with declined viability of ECs [104]; in morbid obese human subjects, insulin-induced mesenteric vasorelaxation concomitant with reduced vascular SIRT3 expression [105]. Dysfunction of mitochondrial redox homeostasis is an important mechanism underlying the dysfunction of Sirt3-deficient ECs. For example, in vitro evidence shows that SIRT3 protects ECs from high glucose induced cytotoxicity through deacetylation of MnSOD [104,106]. By repressing oxidative stress, SIRT3 also protects ECs from damage induced by Ang II, hydrogen peroxide, ox-LDL, ethanol, and hypoxia in vitro [23,107112]. The protective role of SIRT3 in ECs prevents the mouse from vascular damage in diverse models. Sirt3 deletion promotes the impairment in endothelial-dependent vasorelaxation to both insulin and acetylcholine in obese mice, induced by HFD [105,113]. SIRT3 also maintains homeostasis in the microvascular system and regulates angiogenic capabilities in the lungs and the heart. In pulmonary tissues, SIRT3 represses endotoxin-induced loss of pericytes and maintains pericyte/capillary coverage. These effects of SIRT3 subsequently suppress vascular leakage, inflammation, and microvascular dysfunction in the pulmonary tissues, and promote survival of mice [114]. Mice with Sirt3 knockout also exhibit coronary microvascular dysfunction, decreased pericyte/EC coverage together with impaired cardiac recovery post-myocardial ischemia [73]. However, SIRT3 seems to have few effects on hyperlipidemia-mediated atherosclerotic vascular dysfunction. In low-density lipoprotein receptor knockout (Ldlr−/−) mice that are fed HFD (atherosclerosis model), SIRT3 controls systemic levels of oxidative stress, limits expedited weight gain, and allows rapid metabolic adaptation [115]. However, deletion of Sirt3 does not affect plaque burden, features of plaque vulnerability, and inflammatory infiltration [115]. Another similar work also implicated that Sirt3 deficiency induces a mild endothelial dysfunction in mice fed a high-cholesterol diet [113]. Therefore, these results implicate that SIRT3 mildly regulates endothelial dysfunction induced by high-cholesterol diet or endotoxin, but has few effects on hyperlipidemia-mediated atherosclerotic vascular dysfunction.

In addition to SIRT3, in vitro evidence also shows that SIRT4 prevents endothelial dysfunction. SIRT4 represses inflammatory responses in ECs. Inflammatory stimuli, such as lipopolysaccharides, decrease the expression of SIRT4 in human umbilical vein ECs (HUVECs). Down-regulation of SIRT4 indirectly exacerbates the expression of pro-inflammatory cytokines, genes involved in the cyclooxygenase-prostaglandin system, enzymes for extracellular matrix remodeling, and adhesion molecules [116,117]. In human pulmonary microvascular ECs (HPMECs), cigarette smoke extract represses the expression of SIRT4 and induces mononuclear cell adhesion to HPMECs [118]. These findings implicate that SIRT4 may be involved in vascular inflammation and remodeling. However, our current work implicates that Sirt4 knockout did not affect basal or Ang II-induced increase in blood pressure in mice [16].

Taken together, SIRT3 and SIRT4 protect endothelial dysfunction in vitro, but these two factors have few or mild effects on endothelial function during vasculature remodeling in diverse animal models. Interestingly, nuclear members of Sirtuins (e.g. SIRT1 and SIRT6) show significant protection roles in the vascular system [119123]. These facts make mitochondrial Sirtuins much different from their nuclear family members in the vascular system. Thus, systemic works studying the roles of mitochondrial Sirtuins in the vascular system would further promote our understanding of Sirtuin family in the vascular system.

Therapeutic application

Given the important functions of the mitochondrial Sirtuins in CMDs, they are well-reasoned targets for treatment. Several studies have already tried to identify regulators of mitochondrial Sirtuins. Honokiol is a natural biphenolic compound derived from the bark of Magnolia trees. Honokiol could be a novel SIRT3 activator (Figure 2). Honokiol not only enhances SIRT3 expression but is also present in the mitochondrion and binds SIRT3 to increase its activity [58]. Remarkably, honokiol blocks agonist- or pressure overload-mediated cardiac hypertrophy and ameliorates pre-existing cardiac hypertrophy [58]. Moreover, losartan at nonhypotensive dose exerts anti-ischemic effects in part by normalizing the SIRT3 protein level in the ischemic heart [124]. Furthermore, the grape extract resveratrol could also activate SIRT3. Activation of SIRT3 by resveratrol ameliorates cardiac fibrosis and improves cardiac function [125], and attenuates ox-LDL-induced EC apoptosis [111]. Additionally, a recent report showed that SIRT3 mediates the antioxidant effect of the gasotransmitter hydrogen sulphide in ECs [126]. However, no specific activator for mitochondrial Sirtuins is available. Generally, a specific activator is more difficult to develop than an inhibitor. Since our current work demonstrates SIRT4 as a negative regulator of cardiac function during cardiac hypertrophy and fibrosis [16], the specific SIRT4 inhibitor may be a considerable candidate for the treatment of cardiac hypertrophy and failure. A recent work proposed ZINC12421989 as a potential inhibitor of SIRT4 [127]. Further functional study is needed to validate the inhibitory effect of ZINC12421989 on SIRT4 protein and subsequent biological phenotypes.

Chemical structures of activator/inhibitor of mitochondrial Sirtuins

Figure 2
Chemical structures of activator/inhibitor of mitochondrial Sirtuins
Figure 2
Chemical structures of activator/inhibitor of mitochondrial Sirtuins

In addition to drug supplement, nutrient status also regulates the activation of mitochondrial Sirtuins. Controlling nutrient intake may be a more mild and suitable manner to control mitochondrial Sirtuins. CR is a dietary regimen that offers benefits by improving mitochondrial function and quantity control, and subsequently, results in diverse cardiometabolic benefits [4,128]. Long-term CR can up-regulate the level of SIRT3 while has an opposing effect on SIRT4 expression [129]. SIRT3 mediates reduction in oxidative damage and prevents age-related hearing loss under CR [25]. Additionally, SIRT4 is involved in CR-mediated potentiation of amino acid-stimulated insulin secretion [11]. Therefore, the benefits of CR in CMDs may also, at least in part, rely on the regulation of mitochondrial Sirtuins. But further evidence is needed to validate this hypothesis.

The significant contribution of ROS to the pathology of CMDs indicates that therapeutic strategies aimed at reducing oxidative stress may be beneficial. Despite a predominant role of ROS in the pathology of CMDs, large clinical trials have failed to show any benefit of nontargetted oral antioxidants (vitamins A, B6, B12, C, D, and E; β-carotene; folic acid; and selenium) in any CVD [130135]. To some extent, this failure might be ascribed to the nonspecific nature of such agents, which could inhibit both beneficial (physiological) and detrimental (pathological) effects of ROS [136]. Alternatively, recent studies indicate that targetted inhibition of mitochondrial ROS holds promise as a therapeutic strategy for CMDs over the untargetted approach with classical antioxidants [6,7,95,137139]. Mutations of mitochondrial antioxidants (e.g. MnSOD, catalase, glutathione peroxidase, and thioredoxin reductase) were reported to increase the risk of CMDs in humans [140143]. Likewise, mutations in the SIRT3 are associated with myocardial infarction and PAH in humans [40,75]. Targetting mitochondrial Sirtuins for selective suppression of mitochondrial oxidative stress appears to be a potential therapeutic approach for CMDs.

Conclusion and future perspective

The associations between mitochondrial Sirtuins and CMDs are well established at the preclinical level. Mitochondrial Sirtuins not only function in cardiac and vascular tissues but also regulate systemic inflammation, lipid metabolism, insulin resistance, and other risk factors for CMDs. Ample evidence exists that boosting mitochondrial function through modulation of Sirtuins improves whole body and cardiometabolic homeostasis in mice and rats. Current evidence suggests mitochondrial Sirtuins as promising targets for CMD treatment, and specific activators or inhibitors are under development. Despite the achievement of these advances, many issues still remain to be elucidated. First, although the functions of SIRT3 have been well documented in metabolic cardiac and vascular diseases, the physiological and pathological roles of SIRT4 and SIRT5 are far from clear. Second, Sirtuins are associated with ageing and healthspan, less data are available about the functions of mitochondrial Sirtuins in ageing-related decline in cardiac and vascular functions. Third, the interactomes of mitochondrial Sirtuins are quite different from each other, which marks the diversity and complexity of Sirtuin functions within the mitochondrion [21]. Studies of how these physical associations maintain homeostasis under dynamic conditions and how Sirtuins co-operate with each other will further explain how mitochondria regulate CMDs. If we consider mitochondrial Sirtuins as the watchmen of mitochondrial homeostasis, the last but still an important question is who watches the watchmen? It remains unknown how the mitochondrial Sirtuins respond to the cardiometabolic risk factors, such as hypertension, diabetes, obesity, and toxic drugs. Answers to these questions will improve our understanding of mitochondrial Sirtuins in CMDs and facilitate the development of therapeutic approaches.

We thank all the members in Liu lab for discussion of the manuscript.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) [grant numbers 016-I2M-1-015, 2016-I2M-1-016, 2016-I2M-1-011]; the National Natural Science Foundation of China [grant numbers 31571193, 81422002, 91639304, 91339201]; and the National Science and Technology Support Project [grant numbers 2013YQ0309230502, 2014BAI02B01].

Abbreviations

     
  • Ang II

    angiotensin II

  •  
  • BCAA

    branched-chain amino acid

  •  
  • BMC

    bone marrow cell

  •  
  • CMD

    cardiometabolic disease

  •  
  • CR

    caloric restriction

  •  
  • CuZnSOD

    copper- and zinc-containing superoxide dismutase

  •  
  • CVD

    cardiovascular disease

  •  
  • DRP1

    dynamin-related protein 1

  •  
  • DSV

    DNA sequence variant

  •  
  • EC

    endothelial cell

  •  
  • ECHA

    enoyl-CoA hydratase α-subunit

  •  
  • FoxO3a

    Forkhead box O3

  •  
  • ETC

    electron transporter chain

  •  
  • GDH

    glutamate dehydrogenase

  •  
  • GLS

    glutaminase

  •  
  • HDAC

    histone deacetylase

  •  
  • HFD

    high-fat diet

  •  
  • HMGCS2

    3-hydroxy-3-methylglutaryl-CoA synthase 2

  •  
  • HPMEC

    human pulmonary microvascular endothelial cell

  •  
  • IDH2

    isocitrate dehydrogenase 2

  •  
  • IR

    ischemia–reperfusion

  •  
  • LCAD

    long-chain acyl-CoA dehydrogenase

  •  
  • LDLR

    low-density lipoprotein receptor

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MCD

    malonyl-CoA decarboxylase

  •  
  • MnSOD

    manganese-dependent superoxide dismutase

  •  
  • mPTP

    mitochondrial permeability transition pore

  •  
  • NMNAT3

    NMN adenylyltransferase 3

  •  
  • OPA1

    optic atrophy 1

  •  
  • PAH

    pulmonary arterial hypertension

  •  
  • PDC

    pyruvate dehydrogenase complex

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • ROS

    reactive oxygen species

  •  
  • SDH

    succinate dehydrogenase

  •  
  • TAC

    transverse aortic constriction

  •  
  • TCA

    tricarboxylic acid

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