The cellular mitochondrial population undergoes repeated cycles of fission and fusion to maintain its integrity, as well as overall cellular homeostasis. While equilibrium usually exists between the fission–fusion dynamics, their rates are influenced by organellar and cellular metabolic and pathogenic conditions. Under conditions of cellular stress, there is a disruption of this fission and fusion balance and mitochondria undergo either increased fusion, forming a hyperfused meshwork or excessive fission to counteract stress and remove damaged mitochondria via mitophagy. While some previous reports suggest that hyperfusion is initiated to ameliorate cellular stress, recent studies show its negative impact on cellular health in disease conditions. The exact mechanism of mitochondrial hyperfusion and its role in maintaining cellular health and homeostasis, however, remain unclear. In this review, we aim to highlight the different aspects of mitochondrial hyperfusion in either promoting or mitigating stress and also its role in immunity and diseases.

Introduction

Mitochondria, the cellular powerhouses are highly dynamic organelles. Their rapid morphological adaptations are crucial for a plethora of cellular processes like, cell cycle, innate immunity, autophagy, redox signalling, calcium homeostasis, apoptosis, stem cell reprogramming and mitochondrial quality control [1–3]. These bilayered organelles have a complex architecture with an outer mitochondrial membrane (OMM) facing the cytosol, the inner mitochondrial membrane (IMM) that encloses the organellar matrix and harbours DNA (mtDNA). The IMM in turn consists of sub-compartments called cristae and inner boundary membrane (IBM) [4]. Cristae are invaginations protruding into the mitochondrial matrix, whereas the IBM runs parallel to the outer mitochondrial membrane (OMM). Cristae and IBM are connected via narrow tubes or slit-like structures, known as crista junctions (CJs). Recent studies show that components of the electron transport chain (ETC) are confined to the lateral surfaces of the cristae instead of being equally distributed along the IMM [5,6].

The cycles of fission and fusion are referred as ‘mitochondrial dynamics’. Their morphological transitions are co-ordinated by myriad molecular players. These are functionally essential in: (i) maintaining the basic structural integrity of the organelle, (ii) regulating organellar quality control and (iii) establishing and sustaining inter-organellar connections. Mitochondrial fission–fusion processes are closely orchestrated by dynamin-related GTPases.

Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughters. It is regulated by the recruitment and oligomerization of the GTPase Dynamin-related protein 1 (DRP1) onto the OMM. An array of proteins, including mitochondrial dynamics protein MID49, MID51, mitochondrial fission factor (MFF) and mitochondrial fission 1 protein (FIS1) act as adaptors that facilitate the binding of DRP1 onto the OMM and help mediate fission. The role of dynamins (DNM1, DNM2 and DNM3), in this process is still debatable, though some evidence suggest their involvement in the final scission step whereby a mitochondrion divides into two [4,7]. IMM constriction has been proposed to be an independent process regulated by Ca2+ influx [8,9]. Mitochondrial fusion, on the other hand is the union of two mitochondria into one. It is driven by a two-step process: OMM fusion is mediated by the mitofusins (MFNs) 1 and 2; followed by optic atrophy 1 (OPA1) mediated IMM fusion. While these two processes continue in a cyclic manner, some physiological and pathological conditions can shift this balance either way [10].

Mitochondria can also undergo stress-induced mitochondrial hyperfusion (SIMH) [11–13]. This phenotype is characterized by enhanced fusion and the formation of long filamentous mitochondria. The phenotype of mitochondrial hyperfusion has been known for quite some time however, the molecular events regulating this phenomenon still remain obscure. Increased fusion was previously thought to mitigate stress. However, decreased levels of mitochondrial fission can also trigger phenotypes of hyperfusion. An inhibitory phosphorylation of DRP1 at Ser637 residue results in its sequestration in the cytosol and decreased mitochondrial fission mediated hyperfusion. Dephosphorylation of DRP1 at this residue and its subsequent activation is achieved by the Ca2+ dependent phosphatase calcineurin [14]. Likewise, calcineurin deficient skeletal muscles in mice exhibit an elongated mitochondrial network and increased respiratory chain activity [15]. Recent evidence suggests association of mitochondrial hyperfusion with the debilitating neuropathies [16–19].

The present article gives an overview of the series of molecular events that can lead to hyperfusion, the consequences of this phenomenon and the inter-organellar dynamics that influence mitochondrial hyperfusion. Finally, we review how this process of increased fusion adversely affects cellular health and homeostasis, and its connection with diseases.

Cellular events promoting mitochondrial hyperfusion

Cell cycle

During cell division, mitochondria are equally divided amongst the two daughter cells, suggesting a co-ordination between their dynamics and cell cycle. Studies have revealed that mitochondria undergo morphological changes during the progression of cell cycle, tubulation at the G1/S transition and their extensive fragmentation during mitosis [20–22]. Mitochondrial fragmentation during mitosis likely increases the likelihood of their equitable inheritance to daughter cells. On the contrary, the elongated, ‘hyperfused’ network at G1/S is associated with higher ATP production and affects entry into S phase by controlling the levels of cyclin E [21]. Depolarizing mitochondria at early G1 phase blocks cell cycle progression into S phase [21]. It has been demonstrated that knock down of the fission protein DRP1 triggers mitochondrial hyperfusion (Figure 1A), causes delayed G2/M cell cycle transition with unscheduled expression of cyclin E in the G2 phase. This leads to centrosomal overamplification, chromosomal instability and aneuploidy. Interestingly, these events of replicative stress are not mediated by the defects in mitochondrial ATP production and the generation of reactive oxygen species (ROS) [23]. DRP1-deficient stem cells also show a similar property of increased levels of cyclin E, short G1, long S phase and up-regulated progenitor cell markers [24]. Moreover, concurrent knockdown of DRP1 and the mitochondrial fusion protein OPA1 abrogates the elevation of cyclin E levels [22]; thus, implicating OPA1 in the maintenance of the mitochondrial morphology during cell cycle progression. This is also linked to the rhythmic alterations in cyclin levels and phase progression.

Cellular events that lead to hyperfusion.

Figure 1.
Cellular events that lead to hyperfusion.

(A) Various molecular mechanisms skew the mitochondrial fission–fusion balance to promote hyperfusion. Some of the key proteins that get deregulated are indicated. Mitochondria were stained with Mitotracker Deep Red FM (Molecular Probes, Invitrogen) and images acquired using Zeiss LSM710/ConfoCor 3, He-Ne laser at 633 nm. (B) Prolonged stress causes fission in stress-induced hyperfused mitochondria.

Figure 1.
Cellular events that lead to hyperfusion.

(A) Various molecular mechanisms skew the mitochondrial fission–fusion balance to promote hyperfusion. Some of the key proteins that get deregulated are indicated. Mitochondria were stained with Mitotracker Deep Red FM (Molecular Probes, Invitrogen) and images acquired using Zeiss LSM710/ConfoCor 3, He-Ne laser at 633 nm. (B) Prolonged stress causes fission in stress-induced hyperfused mitochondria.

Furthermore, deletion of human fission 1 (hFIS1) phenocopies DRP1 knockdown — with the presence of elongated mitochondria, severe defects in cell cycle progression through G2/M phase and a highly reduced mitotic index. These cells show significant suppression of various cell cycle regulators like cyclin A, cyclin B1, cyclin-dependent kinase1 (CDK1), polo-like kinase1 (PLK1), aurora kinase A and mitotic arrest deficient 2 (MAD2) [25]. Studies suggest that increased phosphorylation of DRP1 at S637, inhibits its fission activity and is closely linked with decreased cell cycle progression and tumorigenesis [14,26–29]. However, there is a paucity of evidence to directly suggest the involvement of S637 phosphorylation during normal cell-cycle progression.

Cellular stress

Cells, under stress, evoke numerous pathways, which can either elicit a positive response nullifying the environmental insult, or a negative response leading to cell death. Mitochondria, being intricately involved in various cellular activities, play a key role in regulating many such stress conditions [30]. Acute oxidative stress or stress generated due to intracellularly accumulated misfolded proteins leads to loss of mitochondrial network in cells destined for apoptosis, along with an increased expression of DRP1 and release of cytochrome c [31–33]. On the contrary, when cells are subjected to modest levels of mitochondrial or ER stress (well below those needed to induce apoptosis), their mitochondria fuse together. They form an interconnected reticulum, similar to that seen with blocked mitochondrial fission [12]. This feature known as stress-induced mitochondrial hyperfusion (SIMH) mitigates the cellular burden by optimizing mitochondrial ATP production [13]. However, prolonged stress reverses this phenotype and leads to mitochondrial fragmentation [12] (Figure 1B).

SIMH is independent of MFN2, BAX/BAK and prohibitins, but requires L-OPA1, MFN1 and the IMM protein, stomatin like Protein 2 (SLP2) (Figure 1A). Interestingly, mitochondria in OPA1-deficient cells under starved conditions are degraded by autophagy (referred as mitophagy). Hence, suggesting that SIMH during nutrient depletion protects from autophagic degradation [34]. It has been recently shown that starvation-induced mitochondrial hyperfusion also depends upon the energy sensor sirtuin 5 (Sirt5). Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate a plethora of processes, like apoptosis, age-associated pathophysiologies, adipocyte, muscle differentiation, gluconeogenesis, to name a few [35]. Loss of SIRT5 induces DRP1 accumulation, mitochondrial fragmentation and degradation via autophagy. In yeast, non-fermentable culture conditions promote increased oxidative phosphorylation and generation of an elongated mitochondrial network [36,37]. Similarly, in HeLa cells, it is reported that the efficiency of oxidative phosphorylation is associated with mitochondrial connectivity, thus suggesting a phenomenon occurring across systems.

Presence of an interconnected mitochondrial network along with increased energy (ATP) production is evidenced during tumour regression and cell cycle progression [21,38]. Certain stressors, like UV-C radiation or treatment with drugs, like actinomycin D and cycloheximide induce hyperfusion via the SLP2-OPA1 pathway [13,39]. Furthermore, under physiological conditions, SIMH promotes NF-κB activation [40]. Altering the reduced to oxidized glutathione (GSH:GSSG) ratio in mouse primary neurons in vitro induces mitochondrial hyperfusion via inducing MFN2 oligomerization. Such changes adversely affect trafficking, the metabolome and neuronal physiology [41]. Alterations in GSH levels and oxidative state are known to be associated with some neurodegenerative diseases [41]. In culture systems, treatment with drugs [like buthionine sulfoximine (BSO), an inhibitor targeting GSH synthesis] has been shown to induce mitochondrial hyperfusion — suggesting a mechanism of transient protection against apoptosis and mitophagy [42,43].

Both oxidative and reductive stress can also lead to mitochondrial hyperfusion via mechanisms that compromise fission. The leucine zipper family transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2) has recently been reported as a master regulator of mitochondrial hyperfusion in response to cellular stress by controlling the expression of hundreds of genes, including those of the proteasome [44]. Increased proteasome activity leads to enhanced DRP1 degradation. Thus, NRF2 activation decreases mitochondrial fission and contributes to hyperfused mitochondrial network formation.

Consequences of mitochondrial hyperfusion

Autophagy

Mitochondrial dynamics are intimately linked with autophagy; reports indicate a reciprocal relationship of mitochondrial hyperfusion and autophagy. Autophagic clearance of dysfunctional mitochondria or mitophagy plays a governing role in mitochondrial maintenance and quality control. Mitochondrial fusion helps to alleviate stress by mixing the contents of partially damaged mitochondria as a form of complementation [34–39]. Thus, elongated or hyperfused mitochondria due to increased rates of fusion have been observed to be spared from autophagic degradation. They also exhibit increased levels of dimerization and ATP synthase activity along with sustained ATP production [45]. Increased mitochondrial fusion and formation of an extended meshwork during nutrient depletion is hence suggested to selectively block the autophagic clearance of these organelles [46] and render cells resistant to cell death (Figure 2) [34,47].

Mitochondrial hyperfusion inhibits mitophagy.

Figure 2.
Mitochondrial hyperfusion inhibits mitophagy.

Cellular senescence, stress or loss of mitochondrial fission factors promotes mitochondrial hyperfusion. This prevents against autophagic clearance of mitochondria in spite of the presence of cellular insults.

Figure 2.
Mitochondrial hyperfusion inhibits mitophagy.

Cellular senescence, stress or loss of mitochondrial fission factors promotes mitochondrial hyperfusion. This prevents against autophagic clearance of mitochondria in spite of the presence of cellular insults.

Also, under conditions of mild stress when autophagy is triggered, cAMP levels increase and protein kinase A (PKA) is activated. PKA phosphorylates DRP1, promotes its retention in the cytoplasm and decreased mitochondrial fission. This in turn phenotypically manifests as hyperfused mitochondria [48]. Decreased mitochondrial fission via disruption of the DRP1 gene leads to an extension of life span in Caenorhabditis elegans and fungal experimental models; however, its deletion in mice leads to embryonic lethality [49–51].

PARKIN and PINK1 mediated mitophagy is observed in neuronal cell lines, depletion of either leads to mitochondrial elongation [52,53]; though opposing reports also exist [10,54]. Under stress, the PINK1/PARKIN pathway is compromised to promote mitochondrial hyperfusion and reduce mitophagy [8]. However, a very recent report refutes its connection with autophagy and hyperfusion [55]. Studies suggest that ubiquitination of MFN2 by PINK1/PARKIN under conditions of stress induces mitophagy [56,57]. In Drosophila models, cells with mutations in MFN2 associated with Charcot–Marie–Tooth type 2A (CMT2A) have mitochondrial hyperfusion and elevated autophagy-related protein 8b (ATG8B) levels [55]. All these together suggest an intricate relationship between cellular stress, mitochondrial hyperfusion and mitophagy.

Apoptosis

A close connection exists between the mitochondrial fission–fusion dynamics and the onset of apoptosis. It is known that during apoptosis, the mitochondrial network undergoes fragmentation. This leads to cytochrome c release, cleavage and activation of caspases, and cell death [58]. While in stressed cells, hyperfusion is usually evoked to abate this and help cell viability, it has been reported that persistent mitochondrial fusion can also incite caspase-dependent cell death. The cell death signals are co-ordinated through activation and cleavage of caspase-8 [59]. It is suggested that DRP1 inhibition leads to enhanced levels of superoxide (O2•−) and pH levels [60]. High levels of O2•− increase levels of GSSG, pH, promoting mitochondrial hyperfusion, release of cytochrome c to the cytosol and culminates in apoptosis in cell culture systems [61]. Furthermore, the DRP1 inhibitor, mitochondrial division inhibitor-1 (MDIVI1) induces dose and time-dependent cell death specifically in a variety of cancer cell lines, while sparing the normal cells [62]. Recent evidence however undermines the effect of MDIVI1 on DRP1 and suggest its role in inhibiting mitochondrial complex I and modifying ROS production [63]. Thus, suggesting a positive correlation between mitochondrial hyperfusion and the onset of apoptosis in at least some experimental systems.

Cancer cells have several hallmarks that define their malignant behaviour; one of these is the replicative potential that allows cells to continually proliferate and contribute to the tumour burden. Mitochondrial division is reported to be linked with this proliferative nature, while mitochondrial hyperfusion has been shown to induce apoptosis (as is reported in breast cancer cell lines) [21,62,64]. It has been observed that the mitochondrial fusion machinery regulator MFN2 has anti-tumorigenic and anti-proliferative properties [65–68]. In mouse xenograft models of human breast cancer cells as well as in patient-derived samples, MFN2 down-regulation has been attributed to the presence of highly fragmented mitochondria and poor prognosis in patients. It has been shown that KRAB associated protein 1 (KAP1) or tripartite motif containing 28 (TRIM28), a transcriptional co-adaptor protein, down-regulates MFN2, restricts mitochondrial hyperfusion and ROS production, thereby contributing to cancer cell survival [69]. Such examples in cancer cells, further support a pro-apoptotic and anti-tumorigenic effect of mitochondrial hyperfusion on cells.

ER-Mitochondria cross-talk and mitochondrial hyperfusion

Mitochondria mediate an inter-organellar cross-talk with the ER via specific interfaces called the mitochondria-associated endoplasmic reticulum membranes (MAM) junctions. These contacts serve to regulate processes like Ca2+ signalling, lipid transport, regulating cellular stress, etc. Recent studies have shown that the ER plays a significant role in regulating mitochondrial dynamics [70] via multiple mechanisms. Hence compromised interactions between these two organelles could affect hyperfusion (Figure 3). First, mitochondrial division is regulated by DNM1/DRP1, which forms helices around mitochondria to mediate fission. DRP1 polymers stabilize membrane curvatures [71]. It has been found that mitochondrial division occurs in places where ER tubules contact mitochondria and mediate constriction prior to DRP1 recruitment. ER-mediated mitochondrial scission is hypothesized to occur in either of the two ways: (1) ER proteins exclusively participating in mitochondrial division and/or (2) ER tubules physically wrapping around the mitochondria, constricting them to a diameter similar to DNM1/DRP1 helices, thus facilitating their recruitment at these interfaces to complete fission [70]. ER-resident proteins hence play a significant role in either recruiting DRP1 to the constriction sites or directly regulating mitochondrial dynamics. Secondly, ER-localized inverted formin 2 (INF2) has been shown to mediate initial mitochondrial constriction of the OMM via actin polymerization, which allows DRP1-driven secondary constriction. It is also involved in the constriction of the IMM [72]. INF2 mutations has also been linked to CMT disease, characterized by the presence of hyperfused mitochondria [8].

ER-mitochondria interactions regulate mitochondrial fission–fusion dynamics.

Figure 3.
ER-mitochondria interactions regulate mitochondrial fission–fusion dynamics.

ER-mitochondria interactions modulate mitochondrial architectural dynamics and lack of this promotes hyperfusion.

Figure 3.
ER-mitochondria interactions regulate mitochondrial fission–fusion dynamics.

ER-mitochondria interactions modulate mitochondrial architectural dynamics and lack of this promotes hyperfusion.

Additionally, under hypoxic conditions, FUN14 domain containing 1 (FUNDC1) accumulates at the MAM by associating with the ER membrane protein calnexin, which subsequently leads to DRP1 mediated fission and mitophagy. Loss of this interaction has been demonstrated to effectuate mitochondrial elongation [73]. Other than the ER-localized proteins, mitochondrial fission adaptor proteins (MID49 and MID51) and MFF at the OMM help recruit DRP1 from the cytosol to mediate fission. The presence of OMM proteins at ER-mitochondrial division foci is suggested to be important for fission [70,74]. Loss of function mutations in MID49 or depletion of MFF has been shown to promote hyperfusion [31,75]. Fetal and Adult Testis Expressed 1 (FATE1)/BJ-HCC-2, a cancer-testis antigen shares a high percentage of sequence homology with the mitochondrial DRP1 receptor MFF. It is primarily localized on the OMM and has recently been suggested as a major survival factor in tumour cells of various origins [76]. Unlike MFF, it is also present at the ER [77]. Interestingly, FATE1 overexpression prevents DRP1 recruitment to mitochondria, and promotes hyperfusion of mitochondrial networks.

Hence mitochondrial hyperfusion is controlled by: (i) its resident adaptors, cytosolic partners that can shuttle to the mitochondria and (ii) ER localized factors. The ER proteins physically interact with the fission proteins to create a ‘stress furrow’ to mediate mitochondrial fission. It is prudent to speculate that loss of this interaction under pathological conditions would lead to mitochondrial hyperfusion.

Apart from physically interacting with the mitochondria to regulate the dynamics, ER might also indirectly promote mitochondrial hyperfusion. The PERK arm of the unfolded protein response (UPR) mediates an ER stress-associated SIMH and protects mitochondria through the transcriptional and translational remodelling of mitochondrial molecular quality control pathways [12].

Mitochondrial hyperfusion in aging, immunity and diseases

Role in cellular aging

Aging is a complex phenomenon that has long been associated with oxidative stress. A skewed balance of ROS production and its removal along with alterations in mitochondrial energetics have emerged as some of the primary contributors of aging [78]. A close relationship exists between mitochondrial fusion–fission dynamics and cellular aging [48,50,51,79–81]. Some recent studies suggest that increased burden of oxidative stress in animal models can extend longevity [82]. Mitochondrial dynamics are believed to be severely reduced in senescent cells [83]. Highly elongated mitochondria, enlarged cristae structures and increased mitochondrial content have been detected during stress-induced premature senescence [84]. A direct correlation so far does not exist between hyperfusion and extended longevity. However, taking together the above reports, it may be argued that the inhibition of mitochondrial fission could lead to elongated mitochondrial networks. This could be pivotal in providing an efficient bioenergetic supply to the aging cell [45]. The associated decrease in fission would probably lead to a beneficial redundancy of oxidative phosphorylation and in turn counteract mitochondrial deficiencies. This mode of mitochondrial hyperfusion stems from decreased mitophagy.

Role in viral infections and innate immunity

Beside an integral role of mitochondria in cell metabolism, the organelle and its dynamics have been reported to be involved in innate immunity [85–87]. Immune cells, when challenged with viral particles elicit a sequence of responses. Interestingly, mitochondrial hyperfusion is reported to mediate viral responses via mitochondrial antiviral signalling (MAVS) [88,89]. dsRNAs have been shown to potentiate mitochondrial elongation; Human Immunodeficiency Virus (HIV) induces increased expression of MFN1 while decreasing DRP1 levels. This promotes a hyperfused elongated network in infected cells [90,91]. Other viruses like Dengue and Severe Acute Respiratory Syndrome (SARS) are suggested to induce mitochondrial hyperfusion via DRP1 inhibition [89,92,93]. In ex vivo systems, SARS viral protein ORF-9b binds to and causes proteasomal degradation of DRP1. MAVS is disrupted, leading to mitochondrial hyperfusion and suppression of interferons (IFNs) [94]. It has been observed that such hyperfused mitochondria promote viral replication, increase cellular respiration, prevent apoptosis, alter MAMs integrity, and negatively impact immune signalling and interferon production. This is regulated via degradation of DRP1 and leads to the disruption of the MAVS, TRAF3, and TRAF 6 signalosome [93,95]. On the contrary, silencing DRP1 during Hepatitis C Virus (HCV) infection enhances IFN production, suggesting a role for mitochondrial fission in promoting cell survival. [94]. Here, mitochondrial elongation by blocking fission adversely affects glycolysis and cellular ATP levels. This leads to increased ROS generation, alters endo-membrane stability and functions, all processes essential for HCV secretion and sustenance [96–98].

Inflammation and inflammasome formation are some of the key components of innate immunity [99]. One such member of the inflammasome, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), linked to mitochondrial dynamics, is an important player that is required for mediating antiviral response. Mitochondrial hyperfusion induced by loss of DRP1 promotes NLRP3 inflammasome activation in macrophages [100]. Also, the formation of the NLRP3–MFN2–MAVS complex during RNA virus infection is required for activation of NLRP3 inflammasome — substantiating the importance of mitochondrial fusion in promoting NLRP3 inflammasome assembly [101]. Alternatively, perturbation in mitochondrial fission also activates NLRP3 inflammasome complex thus promoting an inflammatory response. In otherwords, both inhibition of fission and promotion mitochondrial fusion are crucial in mediating an innate immune response [100].

Role in diseases

Hyperfused mitochondrial network are generated in cells exposed to selective stresses including pro-apoptotic stressors, like UV irradiation and actinomycin D treatment trigger SIMH to alleviate cellular stress via SLP2-OPA1 mediated pathway [13]. Cellular stress also elicits the Kelch like ECH associated protein 1 (KEAP1)-NRF2 pathway to induce mitochondrial hyperfusion via degradation of DRP1 [44]. Thus, implicating a role for mitochondrial hyperfusion in alleviating some cellular stress responses. Studies in stem cells show that exposure to toxicants, like cigarette smoke, induce SIMH and reduce autophagy. Here again, SIMH acts as a survival response to increased mitochondrial oxidative stress [12,13,45]. These mitochondrial alterations combined with autophagic dysfunction preventing clearance of damaged mitochondria, could lead to abnormal stem cell populations. They have ramifications in cellular aging and acquired mitochondriopathies.

Recent reports show that several heterozygous de novo missense mutations in DNM1L (Dynamin 1 like) in humans are associated with abnormal mitochondrial morphology characterized by hyperfused mitochondria. However, this type of hyperfusion is distinct from SIMH [102]. These patients show central nervous system dysgenesis, neurodegeneration, hypotonia, developmental regression, late onset refractory epilepsy, encephalopathy and myoclonus [103]. DRP1 deficiency also leads to hyperfusion; this is associated with ATM dependent cell cycle arrest at G2/M and aneuploidy [23]. Mutations in the outer membrane fusion protein, MFN2 have been widely implicated in the neuropathy, CMT [104–107]. Studies in Drosophila neuronal models reveal two frequent substitution mutations that trigger locomotor deficits associated with mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism, increased mtDNA mutations, and alterations in mitochondrial morphology and organization [55]. It has been noted that some MFN2 mutations associated with CMT disease enhance mitochondrial fusion leading to formation of a more hyperconnected or hyperfused mitochondrial network. It has also been demonstrated that the mitochondrial alterations and locomotor deficits can be rescued by the over-expression of the fission factor DRP1 [55]. Another recent study using fibroblasts from CMT2A patients harbouring different mutations in MFN2 show alterations at the MAM junctions with increased cholesterol metabolism and lipid droplet formation [16]. Though the respiratory chain function in those cells remain unimpaired. While this suggests a link between CMT2A-associated dominant active forms of MFN2 and mitochondrial defects, the molecular mechanisms driving the pathogenesis of this disease continues to remain obscure.

Mutations in coiled-helix coiled-helix domain containing protein 10 (CHCHD10) and its paralogue CHCHD2 have been shown to induce mitochondrial hyperfusion, defects in oxygen consumption and the OXPHOS system [108]. These mutations have been implicated in a variety of diseases including cerebellar ataxia, myopathy, sporadic and familial amyotrophic lateral sclerosis ALS [109–114], sporadic and familial frontotemporal dementia (FTD), autosomal dominant mitochondrial myopathy [115], spinal muscular atrophy (SMA) [116], CMT2 [117], Alzheimer's disease (AD) [112] and Parkinson's disease (PD), to name a few.

Similar effects have also been observed with other cellular proteins that affect mitochondrial dynamics. SCL25A46 is a mitochondrial carrier protein localizing on the outer membrane and is distantly related to Ugo1 [118,119]. It has been shown that a point mutation at L341P promotes rapid degradation of SLC25A46, ultimately manifesting as a rare disease, Pontocerebellar hypoplasia [120]. Decreased SLC25A46 expression is characterized by increased stability and oligomerization of MFN1 and MFN2 on mitochondria, facilitating mitochondrial hyperfusion. The E3 ubiquitin ligases MULAN and MARCH5 co-ordinate ubiquitylation of solute carrier family 25 member 46 (SLC25A46) L341P, leading to degradation by organized activities of P97 and the proteasome from the outer membrane independently of mitophagy and apoptosis [120].

Likewise, in experimental models of the neurodegenerative disorder, AD, reduced DRP1 expression levels have been shown to be associated with elongated mitochondria in patient-derived fibroblasts [121]. Amyloid accumulation is suggested to triggers this reduction in DRP1 protein and or mRNA levels. This is in contradiction to reports which support that depletion of DRP1 blocks mitochondrial fission, results in long interconnected mitochondria and delays cell death [122,123]. In atrial fibrillation (AF) condition, increased mitochondrial fusion is observed. It leads to increased oxidative stress and abnormal Ca2+ homeostasis [124,125]. In C2C12 murine myotube models under conditions of induced hyperfusion (phenocopying the effects of AF), there is an increased colocalization of mitochondria with calcium stores — highlighting the role of mitochondrial hyperfusion and altered MAM interactions in stress-induced arrhythmogenesis [126,127]. Studies have also revealed that mutations in Receptor Expression Enhancing Protein 1 (REEP1), a molecular player prevalent in MAM junctions, promote mitochondrial elongation. Such alterations at the ER-mitochondrial junction protein are detected in patients with hereditary spastic paraplegia (SPG31), a rare neurological disorder [128–130]. Mitochondrial hyperfusion is thus detrimental for cell survival and can lead to the development of various neuropathies. This anomalous mitochondrial form is detected in some cancers, a direct correlation between this organellar phenotype and the resultant pathological outcome is still lacking [69,76] (Figure 4).

Mutations and post-translational modifications in molecular players promoting mitochondrial hyperfusion.

Figure 4.
Mutations and post-translational modifications in molecular players promoting mitochondrial hyperfusion.

Altered fission–fusion dynamics drive mitochondriopathies [16,102,103,108–110,113–117,120,121,129,130].

Figure 4.
Mutations and post-translational modifications in molecular players promoting mitochondrial hyperfusion.

Altered fission–fusion dynamics drive mitochondriopathies [16,102,103,108–110,113–117,120,121,129,130].

Perspectives

  • Mitochondrial hyperfusion is a state maintained by the highly dynamic mitochondria under specific physiological and pathological conditions. This state of mitochondrial elongation might be transient when cells are exposed to various types of stressors, like oxidative or proteostatic. In such situations hyperfusion acts as means of cyto-protection. The fission–fusion balance can be restored from this intermediate condition by removing the causal agents. On the contrary, under certain pathological conditions, the hyperfused state is permanent with loss of mitochondrial fission–fusion balance leading to cyto-toxic effects. Direct evidence linking the underlying molecular mechanisms remain poorly understood.

  • Alterations in fission–fusion dynamics can either skew the balance towards increased fission, generating fragmented mitochondria, or towards enhanced fusion (termed hyperfusion) with large mitochondrial clusters or long filamentous meshwork. Such elongated mitochondrial structures form during G1/S phase of cell cycle or under conditions of cellular stress. ER-mitochondria interactions guide mitochondrial fission — hence perturbations in this also triggers hyperfusion. This state of mitochondrial hyperfusion has been recently linked to a variety of diseases.

  • Multiple lacunae remain in our understanding of the ER-mitochondria dynamics that mediate hyperfusion or are regulated by this process. We propose that research directed towards understanding the role of ER-mitochondrial interactions during the G1/S phase of cell cycle and in stress-induced hyperfusion should be considered. While pathological gene mutations leading to mitochondrial hyperfusion are reported, scope remains: (i) in unravelling the molecular mechanisms of how these mutations alter the fission–fusion balance and (ii) affect mitochondrial energetics.

Competing Interests

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

Author Contribution

R.D. and O.C. conceived the idea and wrote the paper.

Acknowledgements

We thank OC laboratory members for their help and support. R.D. and O.C. are supported by the ‘Integrative Biology on Omics Platform Project’, intramural funding of the Department of Atomic Energy (DAE), Government of India. O.C. is partially funded by SERB, Department of Science & Technology (EMR/2016/002706), Government of India and National Women Bioscientist Award grant, Depart of Biotechnology, Government of India.

Abbreviations

     
  • AD

    Alzheimer's disease

  •  
  • AF

    atrial fibrillation

  •  
  • CMT2A

    Charcot–Marie–Tooth type 2A

  •  
  • DRP1

    Dynamin-related protein 1

  •  
  • ETC

    electron transport chain

  •  
  • FATE1

    Fetal and Adult Testis Expressed 1

  •  
  • HCV

    Hepatitis C Virus

  •  
  • IBM

    inner boundary membrane

  •  
  • IMM

    inner mitochondrial membrane

  •  
  • INF2

    inverted formin 2

  •  
  • MAM

    mitochondria-associated endoplasmic reticulum membranes

  •  
  • MAVS

    mitochondrial antiviral signalling

  •  
  • MDIVI1

    mitochondrial division inhibitor-1

  •  
  • MFF

    mitochondrial fission factor

  •  
  • MFNs

    mitofusins

  •  
  • NLRP3

    NOD-, LRR- and pyrin domain containing protein 3

  •  
  • NRF2

    nuclear factor erythroid 2-related factor 2

  •  
  • OMM

    outer mitochondrial membrane

  •  
  • OPA1

    optic atrophy 1

  •  
  • PKA

    protein kinase A

  •  
  • ROS

    reactive oxygen species

  •  
  • SARS

    Severe Acute Respiratory Syndrome

  •  
  • SIMH

    stress-induced mitochondrial hyperfusion

  •  
  • SLP2

    stomatin like Protein 2

  •  
  • UPR

    unfolded protein response

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679
696