Mitochondria play crucial roles in programmed cell death and aging. Different stimuli activate distinct mitochondrion-dependent cell death pathways, and aging is associated with a progressive increase in mitochondrial damage, culminating in oxidative stress and cellular dysfunction. Mitochondria are highly dynamic organelles that constantly fuse and divide, forming either interconnected mitochondrial networks or separated fragmented mitochondria. These processes are believed to provide a mitochondrial quality control system and enable an effective adaptation of the mitochondrial compartment to the metabolic needs of the cell. The baker's yeast, Saccharomyces cerevisiae, is an established model for programmed cell death and aging research. The present review summarizes how mitochondrial morphology is altered on induction of cell death or on aging and how this correlates with the induction of different cell death pathways in yeast. We highlight the roles of the components of the mitochondrial fusion and fission machinery that affect and regulate cell death and aging.

Introduction

Mitochondria are semi-autonomous organelles that contain their own genome [mtDNA (mitochondrial DNA)], encoding a small subset of mitochondrial proteins. They are bounded by two membranes: the outer and the inner membrane. Mitochondria are essential for various metabolic processes, including oxidative phosphorylation, amino acid metabolism and the formation of iron–sulfur clusters. In addition, mitochondria play crucial roles in the regulation of cell death and aging in various organisms, including humans and yeast [14]. In the budding yeast Saccharomyces cerevisiae, mitochondrial dysfunction, mutations in mtDNA and ROS (reactive oxygen species) produced by mitochondria have been proposed to determine both chronological lifespan (i.e. the survival time of a post-mitotic yeast culture) and replicative lifespan (i.e. the number of cell divisions of an individual mother cell) [35]. In particular, production of detrimental ROS by the NADH:ubiquinone oxidoreductase Ndi1 and the cytochrome bc1 complex of damaged mitochondria was shown to be an important factor promoting cell death [69]. Mitochondrial permeabilization and the release of mitochondrial proteins into the cytosol define distinct mitochondrion-dependent cell death pathways [1013]. Release of cytochrome c correlates with activation of the cell death protease Yca1 (yeast caspase 1), which ultimately executes cell death [13,13a]. In Yca1-independent pathways, Aif1 (apoptosis-inducing factor 1) or endonuclease G (Nuc1) are released from mitochondria and translocate into the nucleus, resulting in the fragmentation of the nuclear genome [10,12]. Mitochondria are also involved in cell death pathways mediated by the alternative cell death protease Kex1 or Ysp1 (yeast suicide protein 1) and Ysp2 [9,1416]. However, the molecular mechanisms of these cell death scenarios remain poorly understood.

Mitochondria are highly dynamic organelles that continuously fuse and divide [17]. In many organisms, including worms and mammals, mitochondrial division promotes the release of cytochrome c to trigger apoptosis [1]. Furthermore, mitochondrial dynamics is thought to counteract aging and constitute an organellar quality control mechanism. Fusion allows complementation and repair processes of damaged mitochondria, whereas fission separates defective organelles from the mitochondrial network, which are then subjected to degradation through mitophagy [17]. In addition to their role in apoptosis and mitochondrial quality control, mitochondrial fusion and fission are needed to optimally adapt mitochondria to the metabolic needs of the cell [17]. In yeast, inhibition of fusion leads to damage and loss of mtDNA [1820]. In contrast, mitochondrial fusion increases mtDNA copy number and ensures high accuracy of the encoded genetic information [21]. While respiratory-active yeast cells harbour an extended tubular mitochondrial network, resting non-dividing cells contain mostly fragmented mitochondria [22].

A conserved molecular machinery mediates mitochondrial fusion and fission in humans and yeast [17]. In yeast, the large GTPase Fzo1, a member of the mitofusin protein family, promotes fusion of the mitochondrial outer membrane, whereas the dynamin-related large GTPase Mgm1 enables fusion of the inner membrane [18,19,23]. Outer and inner membrane fusion is co-ordinated by the outer membrane protein Ugo1, which physically interacts with both Fzo1 and Mgm1 [24]. Division of the outer membrane is performed by the dynamin-related large GTPase Dnm1, which binds via the adaptor proteins Mdv1 or Caf4 to the outer membrane receptor Fis1 and forms a contractile ring that eventually promotes outer membrane division [2527]. An increasing number of accessory and regulatory components are being identified to regulate the fusion and fission processes. These include the rhomboid-related membrane protease Pcp1, which processes Mgm1 [28], and the F-box protein Mdm30, a ubiquitin ligase subunit mediating the turnover of Fzo1 [29].

In the present review, we summarize abnormal mitochondrial morphologies that were observed in yeast models for programmed cell death and that link these morphologies with different cell death pathways. We focus on the effect of the mitochondrial fusion and fission balance on yeast cell death and aging, and we outline how these processes may be relevant under deleterious conditions.

Changes in mitochondrial morphology during yeast cell death and aging

Fragmentation of the mitochondrial network into multiple small organelles has been observed on treatment of yeast cells with multiple different stressors inducing programmed cell death (Figure 1; Table 1). Mitochondrial fragmentation occurs on (i) acidic stress, including acetic acid [16,30,31], propionic acid [16] and formic acid [32], (ii) oxidative stress (H2O2) [33], (iii) treatment with drugs and fungicides (amiodarone [9,15,16], bostrycin [34] and trichothecene [35]), (iv) yeast pheromones (α-factor) [9] and (v) ethanol [36]. A stringent correlation between mitochondrial fragmentation and yeast cell death was further observed in a variety of mutant yeast strains (Table 1), including strains with mutations in (i) rRNA genes (HsTnII) [37], (ii) mRNA turnover genes (lsm4) [38,39], (iii) genes involved in glycoprotein biosynthesis (wbp1-1) [14] and (iv) stress response genes (Δwhi2) [40]. Furthermore, cell death concomitant with mitochondrial fragmentation was observed in yeast cells overexpressing signalling kinases (TPK3) [41], sphingolipid-metabolizing enzymes (YDC1) [42] or overexpressing human proteins, including the pro-apoptotic protein BAX [43], and a Huntington's disease-causing variant of huntingtin [44]. Finally, yeast cells that enter the stationary phase and undergo chronological aging contain fragmented mitochondria [22,45]. The wide variety of death-inducing conditions that correlate with disruption of the mitochondrial network indicates that mitochondrial morphology is strongly influenced by the state of health of the cell. Conversely, conditions that trigger mitochondrial fragmentation frequently result in a decreased chronological lifespan [3739,42].

Mitochondrial fragmentation and aggregation during programmed cell death and aging in yeast

Figure 1
Mitochondrial fragmentation and aggregation during programmed cell death and aging in yeast

See the main text for details.

Figure 1
Mitochondrial fragmentation and aggregation during programmed cell death and aging in yeast

See the main text for details.

Table 1
Yeast cell death and aging associated with abnormal mitochondrial morphologies
 Inducers of cell death Mitochondrial morphology Yeast cell death pathway Reference(s) 
Stressors Acetic acid Fragmentation; FIS1 is not required for fragmentation; actin-dependent formation of mitochondrial aggregates in Δpep4 and Δaac1 Δaac2 Δaac3 Mitochondrial outer membrane permeabilization; cytochrome c release; YCA1, DNM1 and MDV1 promote cell death; FIS1 relieves cell death [30,31
 α-Factor, amiodarone, acetic acid, propionic acid Fragmentation; fragmentation depends on Ysp1and Ysp2 Cell death depends on YSP1 and YSP2; increased mitochondrial membrane potential; ROS accumulation; cytochrome c release [9,15,16
 Bostrycin Fragmentation AIF1-dependent and YCA1-independent cell death; ROS [34
 Ethanol Fragmentation; fragmentation depends on FIS1 but is independent of DNM1 and MDV1; at high concentrations, FIS1 is not required ROS accumulation depends on FIS1; cell death is independent of YCA1, AIF1, cytochrome c, MDV1 and DNM1 [36
 Formic acid Fragmentation Decreased mitochondrial membrane potential; YCA1-independent cell death; ROS accumulation [32
 H2O2 Fragmentation Decreased viability [33
 Trichothecene Fragmentation Mutants of the mitochondrial fusion machinery are resistant to trichothecene-triggered growth deficit [35
Gene deletion/mutation HsTnII Fragmentation Decreased mitochondrial membrane potential; respiratory deficiency; decreased chronological lifespan [37
 lsm4 YCA1-dependent fragmentation YCA1-dependent cell death; ROS accumulation; decreased chronological lifespan [38,39
 wbp1-1 KEX1-dependent fragmentation on abnormal N-glycosylation KEX1-dependent and YCA1-independent cell death; ROS accumulation [14
 Δwhi2 Fragmentation and aggregation; actin-dependent mitochondrial aggregation; mtDNA loss Deletion of WHI2 results in apoptosis triggered by actin aggregation [40
Overexpression BAX Fragmentation in wild-type strain; aggregation in mitophagy-deficient Δuth1 strain AIF1- and YCA1-independent clonogenic cell death; plasma membrane permeabilization on UTH1 deletion [43
 Disease-associated human huntingin Fragmentation and aggregation ROS accumulation; caspase activation; YCA1-dependent nuclear localization of huntingtin aggregates [44
 TPK3 Aggregation Respiratory deficiency and ROS accumulation depends on Tpk3 activity [41
 YDC1 Fragmentation Decreased chronological lifespan and increased apoptosis [42
 Inducers of cell death Mitochondrial morphology Yeast cell death pathway Reference(s) 
Stressors Acetic acid Fragmentation; FIS1 is not required for fragmentation; actin-dependent formation of mitochondrial aggregates in Δpep4 and Δaac1 Δaac2 Δaac3 Mitochondrial outer membrane permeabilization; cytochrome c release; YCA1, DNM1 and MDV1 promote cell death; FIS1 relieves cell death [30,31
 α-Factor, amiodarone, acetic acid, propionic acid Fragmentation; fragmentation depends on Ysp1and Ysp2 Cell death depends on YSP1 and YSP2; increased mitochondrial membrane potential; ROS accumulation; cytochrome c release [9,15,16
 Bostrycin Fragmentation AIF1-dependent and YCA1-independent cell death; ROS [34
 Ethanol Fragmentation; fragmentation depends on FIS1 but is independent of DNM1 and MDV1; at high concentrations, FIS1 is not required ROS accumulation depends on FIS1; cell death is independent of YCA1, AIF1, cytochrome c, MDV1 and DNM1 [36
 Formic acid Fragmentation Decreased mitochondrial membrane potential; YCA1-independent cell death; ROS accumulation [32
 H2O2 Fragmentation Decreased viability [33
 Trichothecene Fragmentation Mutants of the mitochondrial fusion machinery are resistant to trichothecene-triggered growth deficit [35
Gene deletion/mutation HsTnII Fragmentation Decreased mitochondrial membrane potential; respiratory deficiency; decreased chronological lifespan [37
 lsm4 YCA1-dependent fragmentation YCA1-dependent cell death; ROS accumulation; decreased chronological lifespan [38,39
 wbp1-1 KEX1-dependent fragmentation on abnormal N-glycosylation KEX1-dependent and YCA1-independent cell death; ROS accumulation [14
 Δwhi2 Fragmentation and aggregation; actin-dependent mitochondrial aggregation; mtDNA loss Deletion of WHI2 results in apoptosis triggered by actin aggregation [40
Overexpression BAX Fragmentation in wild-type strain; aggregation in mitophagy-deficient Δuth1 strain AIF1- and YCA1-independent clonogenic cell death; plasma membrane permeabilization on UTH1 deletion [43
 Disease-associated human huntingin Fragmentation and aggregation ROS accumulation; caspase activation; YCA1-dependent nuclear localization of huntingtin aggregates [44
 TPK3 Aggregation Respiratory deficiency and ROS accumulation depends on Tpk3 activity [41
 YDC1 Fragmentation Decreased chronological lifespan and increased apoptosis [42

In some of the cell death scenarios described above, mito-chondrial fragmentation is superimposed by aberrant mitochondrial aggregation [40,41,44], which is an active process requiring the actin cytoskeleton [31,40,41]. Aggregated mitochondrial fragments accumulate on disruption of the mitochondrion degradation pathway [31,43], suggesting that most of these organelles are damaged and destined for degradation. Indeed, fragmented and/or aggregated mitochondria were found to be physically and functionally impaired during cell death (Figure 1; Table 1). Mitochondrial deterioration during cell death is characterized by the following events: loss of the mitochondrial membrane potential [32,37], which can be preceded by a strong increase [9], permeabilization of the mitochondrial outer membrane [31], release of cytochrome c [9,31] and loss of mtDNA [40]. As a consequence, cells undergoing cell death frequently become respiratory deficient [37,41]. Notably, the accumulation of ROS appears to be a general hallmark of cell death in cells with fragmented and/or aggregated mitochondria [9,1416,32,34,36,38,39,41,44]. This suggests that damaged mitochondria are a major source of ROS during cell death and thereby actively contribute to the cellular demise (Figure 1).

Cell death correlated with mitochondrial fragmentation either depends on the activity of the yeast cell death protease Yca1 [30,38,39,44] or is promoted independently of Yca1 by factors including the alternative cell death protease Kex1 [14], the mitochondrial cell death factors Aif1, Ysp1 and Ysp2 [9,15,16,34] or by so far unknown factors. Thus it appears that mitochondrial fragmentation concomitant with mitochondrial dysfunction and ROS accumulation are common and crucial events during cell death, whereas the cell death executing pathways may be very different and specified by the inducer of cell death.

Impact of the molecular machinery of mitochondrial fusion and fission on yeast cell death and aging

The correlation of mitochondrial fragmentation and yeast cell death suggests that preventing fragmentation by inhibiting mitochondrial fission (or increasing mitochondrial fusion) might be beneficial for cell survival. Indeed, deletion of the mitochondrial fission factors Dnm1 or Mdv1 results in increased resistance against various cell death stressors, including acetate [30], H2O2 [30,33], the fungicide BAR0329 [46] and the M1 killer virus [47] (Table 2). These observations suggest that Dnm1 and Mdv1 promote cell death. However, deletion of the FIS1 gene encoding the Dnm1 receptor was surprisingly found to have an opposite effect. Cells lacking Fis1 are highly susceptible to ethanol [36] and all kinds of stressors, against which Δdnm1 and Δmdv1 mutants are more resistant [30,33,46,47] (Table 2). Intriguingly, later, it was demonstrated that deletion of the FIS1 gene reproducibly results in the spontaneous acquisition of a secondary mutation in the stress-response gene WHI2 [48]. Yeast cells lacking functional Whi2 are highly sensitive to undergo cell death [40,48], and their mitochondrial network is prone to fragmentation [40] (Table 1). Δfis1 mutants that have acquired secondary whi2 mutations are as sensitive to stress as whi2 mutants in a FIS1 wild-type background, even though they contain a highly interconnected mitochondrial network like Δdnm1 or Δmdv1 strains [48]. Thus the increased susceptibility of Δfis1 cells to undergo cell death is due to mutations in WHI2 rather than inhibition of mitochondrial fission [48]. Therefore it is reasonable to assume that mitochondrial fragmentation by the fission machinery indeed promotes cell death in yeast.

Table 2
Effect of gene deletions on yeast cell death and aging
 Gene deletion Inducers of cell death Cell death pathway on induction Influence of gene deletion on viability/cell death/lifespan Reference(s) 
Mitochondrial fission Δdnm1 H2O2, acetate, BAR0329, M1 killer virus YCA1-dependent cell death; ROS accumulation Decreased cytotoxicity [30,33,46,47
  Ethanol YCA1- and AIF1-independent cell death; ROS accumulation Unaltered cytotoxicity [36
  Aging – Increased chronological and replicative lifespan [33,39,45
 Δfis1 (whi2H2O2, acetate, BAR0329, M1 killer virus YCA1-dependent cell death; ROS accumulation Increased cytotoxicity; WHI2 mutation but not FIS1 deletion confers sensitivity for cell death [30,33,4648
  Ethanol YCA1- and AIF1-independent cell death; ROS accumulation Increased cytotoxicity [36
  Aging – Increased chronological and replicative lifespan [33,39,45
 Δmdv1 H2O2, acetate, BAR0329 YCA1-dependent cell death; ROS accumulation Decreased cytotoxicity [30,46
  Ethanol YCA1- and AIF1-independent cell death; ROS accumulation Unaltered cytotoxicity [36
Mitochondrial fusion Δfzo1 Aging – Increased chronological lifespan [39
  Trichothecene – Growth deficit relieved [35
 Δmdm30 H2O2 – Decreased cytotoxicity [33
  Aging – Increased chronological lifespan [33,39
 Δpcp1 Trichothecene – Growth deficit relieved [35
 Gene deletion Inducers of cell death Cell death pathway on induction Influence of gene deletion on viability/cell death/lifespan Reference(s) 
Mitochondrial fission Δdnm1 H2O2, acetate, BAR0329, M1 killer virus YCA1-dependent cell death; ROS accumulation Decreased cytotoxicity [30,33,46,47
  Ethanol YCA1- and AIF1-independent cell death; ROS accumulation Unaltered cytotoxicity [36
  Aging – Increased chronological and replicative lifespan [33,39,45
 Δfis1 (whi2H2O2, acetate, BAR0329, M1 killer virus YCA1-dependent cell death; ROS accumulation Increased cytotoxicity; WHI2 mutation but not FIS1 deletion confers sensitivity for cell death [30,33,4648
  Ethanol YCA1- and AIF1-independent cell death; ROS accumulation Increased cytotoxicity [36
  Aging – Increased chronological and replicative lifespan [33,39,45
 Δmdv1 H2O2, acetate, BAR0329 YCA1-dependent cell death; ROS accumulation Decreased cytotoxicity [30,46
  Ethanol YCA1- and AIF1-independent cell death; ROS accumulation Unaltered cytotoxicity [36
Mitochondrial fusion Δfzo1 Aging – Increased chronological lifespan [39
  Trichothecene – Growth deficit relieved [35
 Δmdm30 H2O2 – Decreased cytotoxicity [33
  Aging – Increased chronological lifespan [33,39
 Δpcp1 Trichothecene – Growth deficit relieved [35

Remarkably, Dnm1- and Mdv1-promoted cell death depends on Yca1 in all the scenarios tested so far [30,46,47]. Thus it appears that a cell death pathway executed by the dynamin-related mitochondrial fission machinery and caspase-related factors has been conserved from yeast to worms and mammals [1]. On the other hand, stressing yeast cells with high concentrations of ethanol or acetic acid results in mitochondrial fragmentation that is independent of the mitochondrial fission factors Dnm1, Mdv1 and/or Fis1 [30,36] (Table 1). In this pathway, cell death is mediated by alternative cell death factors, such as Aif1, Kex1, Ysp1 and Ysp2 [9,1416,34] (Figure 1; Table 1). These observations suggest that detrimental environmental conditions may induce mitochondrial fragmentation and cell death in a way that is independent of the known fission machinery and Yca1.

As mitochondrial fragmentation facilitates cell death, it can be expected that inhibition of mitochondrial fusion might have a similar effect (Figure 1). However, a genome-wide screening for resistance against the mycotoxin trichothecene demonstrated that yeast strains with the mitochondrial fusion genes FZO1 and PCP1 deleted are highly resistant to the toxin, rather than more susceptible to it [35] (Table 2). Similarly, a yeast strain with MDM30 deleted demonstrated an increased resistance to H2O2 treatment [33] (Table 2). These unexpected phenotypes might be explained by the fact that fusion-deficient yeast strains have a high tendency to lose their mtDNA [1820]. Since cells depleted of mtDNA were shown to be completely resistant to trichothecene treatment [35], these results suggest that the beneficial effect of the deletion of mitochondrial fusion factors can be ascribed to a loss of mtDNA rather than a blocking of fusion.

Conditions that promote mitochondrial fragmentation and cell death lead to a decreased chronological lifespan [3739,42] (Table 1). On the other hand, caloric restriction is associated with an increased chronological lifespan in yeast [3,49,50] and leads to the down-regulation of the fission factors Fis1, Mdv1 and Caf4 concomitant with up-regulation of the fusion factor Mgm1 [51]. Thus inhibition of mitochondrial fragmentation may be associated with a prolonged lifespan. Indeed, deletion of the mitochondrial fission gene DNM1 was shown to significantly increase both the chronological and the replicative lifespan of yeast cells [33,39,45] (Table 2). Consistent with this, deletion of the FIS1 gene also resulted in increased chronological and replicative lifespan, in spite of the presence of its pro-death secondary mutation in the stress response gene WHI2 [33,39,45] (Table 2). These observations suggest that during aging the pro-survival phenotype of the Δfis1 deletion overrules the pro-death function of the whi2 mutation that appears to be dominant only in younger cultures.

Surprisingly, deletion of the fusion gene FZO1 resulted in a slightly prolonged chronological lifespan [33,39], and cells with MDM30 deleted demonstrated even a 60% increase in chronological lifespan [33,39]. Future experiments will have to show whether the fusion-incompetence or the lack of respiratory capacity and decreased mtDNA stability are responsible for longevity in these mutants.

Conclusions

A variety of different cell death-inducing conditions, including cell stress, gene mutations and overexpression, result in mitochondrial dysfunction accompanied by a boost of ROS and the release of mitochondrial pro-death factors, such as cytochrome c and Aif1. In addition to the deterioration of mitochondrial functions, fragmentation of the mitochondrial network appears to be a hallmark of various cell death pathways, including YCA1-dependent and -independent pathways. Whereas inhibition of mitochondrial fission was shown to result in increased stress resistance and prolonged chronological and replicative lifespan, the role of mitochondrial fusion is less clear. Future studies are required to determine whether the known components of the mitochondrial fusion and fission machineries play a general role in yeast cell death and aging or whether additional factors exist.

8th International Meeting on Yeast Apoptosis: An Independent Meeting held at Keynes College, University of Kent, Canterbury, U.K., 2–6 May 2011. Organized and Edited by Paula Ludovico (University of Minho, Braga, Portugal).

Abbreviations

     
  • Aif1

    apoptosis-inducing factor 1

  •  
  • mtDNA

    mitochondrial DNA

  •  
  • ROS

    reactive oxygen species

  •  
  • Yca1

    yeast caspase 1

  •  
  • Ysp

    yeast suicide protein

Funding

We are grateful to the Deutsche Forschungsgemeinschaft for funding our work.

References

References
1
Suen
D.F.
Norris
K.L.
Youle
R.J.
Mitochondrial dynamics and apoptosis
Genes Dev.
2008
, vol. 
22
 (pg. 
1577
-
1590
)
2
Cheng
W.C.
Leach
K.M.
Hardwick
J.M.
Mitochondrial death pathways in yeast and mammalian cells
Biochim. Biophys. Acta
2008
, vol. 
1783
 (pg. 
1272
-
1279
)
3
Fabrizio
P.
Longo
V.D.
Chronological aging-induced apoptosis in yeast
Biochim. Biophys. Acta
2008
, vol. 
1783
 (pg. 
1280
-
1285
)
4
Laun
P.
Heeren
G.
Rinnerthaler
M.
Rid
R.
Kössler
S.
Koller
L.
Breitenbach
M.
Senescence and apoptosis in yeast mother cell-specific aging and in higher cells: a short review
Biochim. Biophys. Acta
2008
, vol. 
1783
 (pg. 
1328
-
1334
)
5
Herker
E.
Jungwirth
H.
Lehmann
K.A.
Maldener
C.
Fröhlich
K.U.
Wissing
S.
Büttner
S.
Fehr
M.
Sigrist
S.
Madeo
F.
Chronological aging leads to apoptosis in yeast
J. Cell Biol.
2004
, vol. 
164
 (pg. 
501
-
507
)
6
Braun
R.J.
Sommer
C.
Carmona-Gutierrez
D.
Khoury
C.M.
Ring
J.
Büttner
S.
Madeo
F.
Neurotoxic 43-kDa TAR DNA-binding protein (TDP-43) triggers mitochondrion-dependent programmed cell death in yeast
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
19958
-
19972
)
7
Braun
R.J.
Zischka
H.
Madeo
F.
Eisenberg
T.
Wissing
S.
Büttner
S.
Engelhardt
S.M.
Büringer
D.
Ueffing
M.
Crucial mitochondrial impairment upon CDC48 mutation in apoptotic yeast
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
25757
-
25767
)
8
Li
W.
Sun
L.
Liang
Q.
Wang
J.
Mo
W.
Zhou
B.
Yeast AMID homologue Ndi1p displays respiration-restricted apoptotic activity and is involved in chronological aging
Mol. Biol. Cell
2006
, vol. 
17
 (pg. 
1802
-
1811
)
9
Pozniakovsky
A.I.
Knorre
D.A.
Markova
O.V.
Hyman
A.A.
Skulachev
V.P.
Severin
F.F.
Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast
J. Cell Biol.
2005
, vol. 
168
 (pg. 
257
-
269
)
10
Büttner
S.
Eisenberg
T.
Carmona-Gutierrez
D.
Ruli
D.
Knauer
H.
Ruckenstuhl
C.
Sigrist
C.
Wissing
S.
Kollroser
M.
Fröhlich
K.U.
, et al. 
Endonuclease G regulates budding yeast life and death
Mol. Cell
2007
, vol. 
25
 (pg. 
233
-
246
)
11
Pereira
C.
Camougrand
N.
Manon
S.
Sousa
M.J.
Corte-Real
M.
ADP/ATP carrier is required for mitochondrial outer membrane permeabilization and cytochrome c release in yeast apoptosis
Mol. Microbiol.
2007
, vol. 
66
 (pg. 
571
-
582
)
12
Wissing
S.
Ludovico
P.
Herker
E.
Büttner
S.
Engelhardt
S.M.
Decker
T.
Link
A.
Proksch
A.
Rodrigues
F.
Corte-Real
M.
, et al. 
An AIF orthologue regulates apoptosis in yeast
J. Cell Biol.
2004
, vol. 
166
 (pg. 
969
-
974
)
13
Ludovico
P.
Rodrigues
F.
Almeida
A.
Silva
M.T.
Barientos
A.
Côrte-Real
M.
Cytochrome c release and mitochondria involvement in programmed cell death induced by acetic acid in Saccharomyces cerevisiae
Mol. Biol. Cell
2002
, vol. 
13
 (pg. 
2598
-
2606
)
13a
Madeo
F.
Herker
E.
Maldener
C.
Wissing
S.
Lächelt
S.
Herlan
M.
Fehr
M.
Lauber
K.
Sigrist
S.J.
Wesselborg
S.
Fröhlich
K.U.
A caspase-related protease regulates apoptosis in yeast
Mol. Cell
2002
, vol. 
9
 (pg. 
911
-
917
)
14
Hauptmann
P.
Lehle
L.
Kex1 protease is involved in yeast cell death induced by defective N-glycosylation, acetic acid, and chronological aging
J. Biol. Chem.
2008
, vol. 
283
 (pg. 
19151
-
19163
)
15
Knorre
D.A.
Ojovan
S.M.
Saprunova
V.B.
Sokolov
S.S.
Bakeeva
L.E.
Severin
F.F.
Mitochondrial matrix fragmentation as a protection mechanism of yeast Saccharomyces cerevisiae
Biochemistry
2008
, vol. 
73
 (pg. 
1254
-
1259
)
16
Sokolov
S.
Knorre
D.
Smirnova
E.
Markova
O.
Pozniakovsky
A.
Skulachev
V.
Severin
F.
Ysp2 mediates death of yeast induced by amiodarone or intracellular acidification
Biochim. Biophys. Acta
2006
, vol. 
1757
 (pg. 
1366
-
1370
)
17
Westermann
B.
Mitochondrial fusion and fission in cell life and death
Nat. Rev. Mol. Cell Biol.
2010
, vol. 
11
 (pg. 
872
-
884
)
18
Hermann
G.J.
Thatcher
J.W.
Mills
J.P.
Hales
K.G.
Fuller
M.T.
Nunnari
J.
Shaw
J.M.
Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p
J. Cell Biol.
1998
, vol. 
143
 (pg. 
359
-
373
)
19
Rapaport
D.
Brunner
M.
Neupert
W.
Westermann
B.
Fzo1p is a mitochondrial outer membrane protein essential for the biogenesis of functional mitochondria in Saccharomyces cerevisiae
J. Biol. Chem.
1998
, vol. 
273
 (pg. 
20150
-
20155
)
20
Merz
S.
Westermann
B.
Genome-wide deletion mutant analysis reveals genes required for respiratory growth, mitochondrial genome maintenance and mitochondrial protein synthesis in Saccharomyces cerevisiae
Genome Biol.
2009
, vol. 
10
 pg. 
R95
 
21
Hori
A.
Yoshida
M.
Ling
F.
Mitochondrial fusion increases the mitochondrial DNA copy number in budding yeast
Genes Cells
2011
, vol. 
16
 (pg. 
527
-
544
)
22
Merz
S.
Hammermeister
M.
Altmann
K.
Dürr
M.
Westermann
B.
Molecular machinery of mitochondrial dynamics in yeast
Biol. Chem.
2007
, vol. 
388
 (pg. 
917
-
926
)
23
Wong
E.D.
Wagner
J.A.
Gorsich
S.W.
McCaffery
J.M.
Shaw
J.M.
Nunnari
J.
The dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria
J. Cell Biol.
2000
, vol. 
151
 (pg. 
341
-
352
)
24
Sesaki
H.
Jensen
R.E.
Ugo1p links the Fzo1p and Mgm1p GTPases for mitochondrial fusion
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
28298
-
28303
)
25
Mozdy
A.D.
McCaffery
J.M.
Shaw
J.M.
Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p
J. Cell Biol.
2000
, vol. 
151
 (pg. 
367
-
380
)
26
Tieu
Q.
Nunnari
J.
Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division
J. Cell Biol.
2000
, vol. 
151
 (pg. 
353
-
366
)
27
Griffin
E.E.
Graumann
J.
Chan
D.C.
The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria
J. Cell Biol.
2005
, vol. 
170
 (pg. 
237
-
248
)
28
Herlan
M.
Vogel
F.
Bornhövd
C.
Neupert
W.
Reichert
A.S.
Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
27781
-
27788
)
29
Fritz
S.
Weinbach
N.
Westermann
B.
Mdm30 is an F-box protein required for maintenance of fusion-competent mitochondria in yeast
Mol. Biol. Cell
2003
, vol. 
14
 (pg. 
2303
-
2313
)
30
Fannjiang
Y.
Cheng
W.C.
Lee
S.J.
Qi
B.
Pevsner
J.
McCaffery
J.M.
Hill
R.B.
Basanez
G.
Hardwick
J.M.
Mitochondrial fission proteins regulate programmed cell death in yeast
Genes Dev.
2004
, vol. 
18
 (pg. 
2785
-
2797
)
31
Pereira
C.
Chaves
S.
Alves
S.
Salin
B.
Camougrand
N.
Manon
S.
Sousa
M.J.
Corte-Real
M.
Mitochondrial degradation in acetic acid-induced yeast apoptosis: the role of Pep4 and the ADP/ATP carrier
Mol. Microbiol.
2010
, vol. 
76
 (pg. 
1398
-
1410
)
32
Du
L.
Su
Y.
Sun
D.
Zhu
W.
Wang
J.
Zhuang
X.
Zhou
S.
Lu
Y.
Formic acid induces Yca1p-independent apoptosis-like cell death in the yeast Saccharomyces cerevisiae
FEMS Yeast Res.
2008
, vol. 
8
 (pg. 
531
-
539
)
33
Palermo
V.
Falcone
C.
Mazzoni
C.
Apoptosis and aging in mitochondrial morphology mutants of S. cerevisiae
Folia Microbiol.
2007
, vol. 
52
 (pg. 
479
-
483
)
34
Xu
C.
Wang
J.
Gao
Y.
Lin
H.
Du
L.
Yang
S.
Long
S.
She
Z.
Cai
X.
Zhou
S.
Lu
Y.
The anthracenedione compound bostrycin induces mitochondria-mediated apoptosis in the yeast Saccharomyces cerevisiae
FEMS Yeast Res.
2010
, vol. 
10
 (pg. 
297
-
308
)
35
McLaughlin
J.E.
Bin-Umer
M.A.
Tortora
A.
Mendez
N.
McCormick
S.
Tumer
N.E.
A genome-wide screen in Saccharomyces cerevisiae reveals a critical role for the mitochondria in the toxicity of a trichothecene mycotoxin
Proc. Natl. Acad. Sci. U.S.A.
2009
, vol. 
106
 (pg. 
21883
-
21888
)
36
Kitagaki
H.
Araki
Y.
Funato
K.
Shimoi
H.
Ethanol-induced death in yeast exhibits features of apoptosis mediated by mitochondrial fission pathway
FEBS Lett.
2007
, vol. 
581
 (pg. 
2935
-
2942
)
37
Aerts
A.M.
Zabrocki
P.
Govaert
G.
Mathys
J.
Carmona-Gutierrez
D.
Madeo
F.
Winderickx
J.
Cammue
B.P.
Thevissen
K.
Mitochondrial dysfunction leads to reduced chronological lifespan and increased apoptosis in yeast
FEBS Lett.
2009
, vol. 
583
 (pg. 
113
-
117
)
38
Mazzoni
C.
Herker
E.
Palermo
V.
Jungwirth
H.
Eisenberg
T.
Madeo
F.
Falcone
C.
Yeast caspase 1 links messenger RNA stability to apoptosis in yeast
EMBO Rep.
2005
, vol. 
6
 (pg. 
1076
-
1081
)
39
Palermo
V.
Falcone
C.
Calvani
M.
Mazzoni
C.
Acetyl-L-carnitine protects yeast cells from apoptosis and aging and inhibits mitochondrial fission
Aging Cell
2010
, vol. 
9
 (pg. 
570
-
579
)
40
Leadsham
J.E.
Miller
K.
Ayscough
K.R.
Colombo
S.
Martegani
E.
Sudbery
P.
Gourlay
C.W.
Whi2p links nutritional sensing to actin-dependent Ras–cAMP–PKA regulation and apoptosis in yeast
J. Cell Sci.
2009
, vol. 
122
 (pg. 
706
-
715
)
41
Leadsham
J.E.
Gourlay
C.W.
cAMP/PKA signaling balances respiratory activity with mitochondria dependent apoptosis via transcriptional regulation
BMC Cell Biol.
2010
, vol. 
11
 pg. 
92
 
42
Aerts
A.M.
Zabrocki
P.
Francois
I.E.
Carmona-Gutierrez
D.
Govaert
G.
Mao
C.
Smets
B.
Madeo
F.
Winderickx
J.
Cammue
B.P.
Thevissen
K.
Ydc1p ceramidase triggers organelle fragmentation, apoptosis and accelerated ageing in yeast
Cell. Mol. Life Sci.
2008
, vol. 
65
 (pg. 
1933
-
1942
)
43
Kissova
I.
Plamondon
L.T.
Brisson
L.
Priault
M.
Renouf
V.
Schaeffer
J.
Camougrand
N.
Manon
S.
Evaluation of the roles of apoptosis, autophagy, and mitophagy in the loss of plating efficiency induced by Bax expression in yeast
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
36187
-
36197
)
44
Sokolov
S.
Pozniakovsky
A.
Bocharova
N.
Knorre
D.
Severin
F.
Expression of an expanded polyglutamine domain in yeast causes death with apoptotic markers
Biochim. Biophys. Acta
2006
, vol. 
1757
 (pg. 
660
-
666
)
45
Scheckhuber
C.Q.
Erjavec
N.
Tinazli
A.
Hamann
A.
Nystrom
T.
Osiewacz
H.D.
Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models
Nat. Cell Biol.
2007
, vol. 
9
 (pg. 
99
-
105
)
46
Bink
A.
Govaert
G.
Francois
I.E.
Pellens
K.
Meerpoel
L.
Borgers
M.
Van Minnebruggen
G.
Vroome
V.
Cammue
B.P.
Thevissen
K.
A fungicidal piperazine-1-carboxamidine induces mitochondrial fission-dependent apoptosis in yeast
FEMS Yeast Res.
2010
, vol. 
10
 (pg. 
812
-
818
)
47
Ivanovska
I.
Hardwick
J.M.
Viruses activate a genetically conserved cell death pathway in a unicellular organism
J. Cell Biol.
2005
, vol. 
170
 (pg. 
391
-
399
)
48
Cheng
W.C.
Teng
X.
Park
H.K.
Tucker
C.M.
Dunham
M.J.
Hardwick
J.M.
Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects
Cell Death Differ.
2008
, vol. 
15
 (pg. 
1838
-
1846
)
49
Rockenfeller
P.
Madeo
F.
Ageing and eating
Biochim. Biophys. Acta
2010
, vol. 
1803
 (pg. 
499
-
506
)
50
Fontana
L.
Partridge
L.
Longo
V.D.
Extending healthy life span: from yeast to humans
Science
2010
, vol. 
328
 (pg. 
321
-
326
)
51
Goldberg
A.A.
Bourque
S.D.
Kyryakov
P.
Gregg
C.
Boukh-Viner
T.
Beach
A.
Burstein
M.T.
Machkalyan
G.
Richard
V.
Rampersad
S.
, et al. 
Effect of calorie restriction on the metabolic history of chronologically aging yeast
Exp. Gerontol.
2009
, vol. 
44
 (pg. 
555
-
571
)