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1.  Loss of Prohibitin Induces Mitochondrial Damages Altering β-Cell Function and Survival and Is Responsible for Gradual Diabetes Development 
Diabetes  2013;62(10):3488-3499.
Prohibitins are highly conserved proteins mainly implicated in the maintenance of mitochondrial function and architecture. Their dysfunctions are associated with aging, cancer, obesity, and inflammation. However, their possible role in pancreatic β-cells remains unknown. The current study documents the expression of prohibitins in human and rodent islets and their key role for β-cell function and survival. Ablation of Phb2 in mouse β-cells sequentially resulted in impairment of mitochondrial function and insulin secretion, loss of β-cells, progressive alteration of glucose homeostasis, and, ultimately, severe diabetes. Remarkably, these events progressed over a 3-week period of time after weaning. Defective insulin supply in β-Phb2−/− mice was contributed by both β-cell dysfunction and apoptosis, temporarily compensated by increased β-cell proliferation. At the molecular level, we observed that deletion of Phb2 caused mitochondrial abnormalities, including reduction of mitochondrial DNA copy number and respiratory chain complex IV levels, altered mitochondrial activity, cleavage of L-optic atrophy 1, and mitochondrial fragmentation. Overall, our data demonstrate that Phb2 is essential for metabolic activation of mitochondria and, as a consequence, for function and survival of β-cells.
doi:10.2337/db13-0152
PMCID: PMC3781460  PMID: 23863811
2.  Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion 
The Journal of Cell Biology  2014;204(3):303-312.
The developmental and motor defects evident in flies depleted of the mitofusin Marf can be ameliorated by treatments that reduce ER stress, confirming an active role for ER stress in the observed phenotypes.
Ablation of the mitochondrial fusion and endoplasmic reticulum (ER)–tethering protein Mfn2 causes ER stress, but whether this is just an epiphenomenon of mitochondrial dysfunction or a contributor to the phenotypes in mitofusin (Mfn)-depleted Drosophila melanogaster is unclear. In this paper, we show that reduction of ER dysfunction ameliorates the functional and developmental defects of flies lacking the single Mfn mitochondrial assembly regulatory factor (Marf). Ubiquitous or neuron- and muscle-specific Marf ablation was lethal, altering mitochondrial and ER morphology and triggering ER stress that was conversely absent in flies lacking the fusion protein optic atrophy 1. Expression of Mfn2 and ER stress reduction in flies lacking Marf corrected ER shape, attenuating the developmental and motor defects. Thus, ER stress is a targetable pathogenetic component of the phenotypes caused by Drosophila Mfn ablation.
doi:10.1083/jcb.201306121
PMCID: PMC3912536  PMID: 24469638
3.  Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency 
Cell  2013;155(1):160-171.
Summary
Respiratory chain complexes assemble into functional quaternary structures called supercomplexes (RCS) within the folds of the inner mitochondrial membrane, or cristae. Here, we investigate the relationship between respiratory function and mitochondrial ultrastructure and provide evidence that cristae shape determines the assembly and stability of RCS and hence mitochondrial respiratory efficiency. Genetic and apoptotic manipulations of cristae structure affect assembly and activity of RCS in vitro and in vivo, independently of changes to mitochondrial protein synthesis or apoptotic outer mitochondrial membrane permeabilization. We demonstrate that, accordingly, the efficiency of mitochondria-dependent cell growth depends on cristae shape. Thus, RCS assembly emerges as a link between membrane morphology and function.
Graphical Abstract
Highlights
•Dissociation of cristae remodeling from OMM permeabilization•Cristae shape determines assembly of respiratory chain supercomplexes•Efficiency of mitochondrial respiration and cellular growth depends on cristae shape
The ability to perturb cristae shape without affecting other key aspects of mitochondrial physiology reveals that membrane shape influences supercomplex assembly and stability to regulate mitochondrial respiration and cellular respiratory growth. Quaternary structures such as supercomplexes therefore emerge as a link between membrane morphology and function.
doi:10.1016/j.cell.2013.08.032
PMCID: PMC3790458  PMID: 24055366
4.  OPA1 promotes pH flashes that spread between contiguous mitochondria without matrix protein exchange 
The EMBO Journal  2013;32(13):1927-1940.
The chemical nature and functional significance of mitochondrial flashes associated with fluctuations in mitochondrial membrane potential is unclear. Using a ratiometric pH probe insensitive to superoxide, we show that flashes reflect matrix alkalinization transients of ∼0.4 pH units that persist in cells permeabilized in ion-free solutions and can be evoked by imposed mitochondrial depolarization. Ablation of the pro-fusion protein Optic atrophy 1 specifically abrogated pH flashes and reduced the propagation of matrix photoactivated GFP (paGFP). Ablation or invalidation of the pro-fission Dynamin-related protein 1 greatly enhanced flash propagation between contiguous mitochondria but marginally increased paGFP matrix diffusion, indicating that flashes propagate without matrix content exchange. The pH flashes were associated with synchronous depolarization and hyperpolarization events that promoted the membrane potential equilibration of juxtaposed mitochondria. We propose that flashes are energy conservation events triggered by the opening of a fusion pore between two contiguous mitochondria of different membrane potentials, propagating without matrix fusion to equilibrate the energetic state of connected mitochondria.
Mitochondrial fusion events and transient changes in matrix pH linked to membrane depolarization are found to underlie mitochondrial flashes, whose propagation may help equilibrate energy states between connected mitochondria.
doi:10.1038/emboj.2013.124
PMCID: PMC3981180  PMID: 23714779
bioenergetics; cell signalling; metabolism
5.  Mice Deficient in the Respiratory Chain Gene Cox6a2 Are Protected against High-Fat Diet-Induced Obesity and Insulin Resistance 
PLoS ONE  2013;8(2):e56719.
Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.
doi:10.1371/journal.pone.0056719
PMCID: PMC3584060  PMID: 23460811
6.  The Pathophysiology of LETM1 
The Journal of General Physiology  2012;139(6):445-454.
doi:10.1085/jgp.201110757
PMCID: PMC3362517  PMID: 22641639
7.  Mitochondrial elongation during autophagy 
Autophagy  2011;7(10):1251-1253.
Mitochondrial morphological and structural changes play a role in several cellular processes, including apoptosis. We recently reported that mitochondrial elongation is also critical to sustain cell viability during macroautophagy. During macroautophagy unopposed mitochondrial fusion leads to organelle elongation both in vitro and in vivo. Longer mitochondria are protected from being degraded and possess more cristae where activity of the ATP synthase is increased, optimizing ATP production in times of nutrient restriction.
doi:10.4161/auto.7.10.16771
PMCID: PMC3242616  PMID: 21743300
mitochondria; autophagy; fusion; cAMP; PKA; DRP-1; cell death
8.  The antiapoptotic OPA1/Parl couple participates in mitochondrial adaptation to heat shock☆ 
Biochimica et Biophysica Acta  2012;1817(10):1886-1893.
The mitochondria-shaping protein optic atrophy 1 (OPA1) has genetically distinguishable roles in mitochondrial morphology and apoptosis. The latter depends on the presenilin associated rhomboid like (PARL) protease, essential for the accumulation of a soluble intermembrane space form of OPA1 (IMS-OPA1). Here we show that OPA1 and PARL participate in the heat shock response, a stereotypical cellular process of adaptation to thermal stress. Upon heat shock, long forms of OPA1 are lost and mitochondria fragment. However, mitochondrial fusion is dispensable to maintain viability, whereas IMS-OPA1 is required. Upon conditioning—a process of mild heat shock and recovery—IMS-OPA1 accumulates, OPA1 oligomers increase and mitochondria release less cytochrome c, ultimately resulting in cellular resistance to subsequent apoptotic inducers. In Parl−/− cells accumulation of IMS-OPA1 is blunted and conditioning fails to protect from cytochrome c release and apoptosis. Thus, the OPA1/PARL dependent pathway of cristae remodeling is implicated in heat shock. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).
Highlights
► Heat shock causes cleavage of the cristae regulator OPA1. ► Heat shock causes PARL-dependent accumulation of soluble antiapoptotic OPA1. ► Soluble OPA1 confers secondary resistance to apoptosis to heat shocked cells. ► OPA1 is essential also for heat shock conditioning.
doi:10.1016/j.bbabio.2012.05.001
PMCID: PMC3686154  PMID: 22579715
BAK, Bcl-2 associated killer; BAX, Bcl-2 associated protein X; BCL-2, B-cell lymphoma 2; DRP1, dynamin related protein 1; FCCP, cyanide m-fluorophenylhydrazone; FIS1, fission 1; HSP, heat shock protein; IMM, inner mitochondrial membrane; IMS, intermembrane space; MEFs, mouse embryonic fibroblasts; OMM, outer mitochondrial membrane; OPA1, optic atrophy 1; MFN, mitofusin; PARL, presenilin associated rhomboid like; Mitochondrion; OPA1; PARL; Heat shock response; Cytochrome c release; Apoptosis
9.  Optic Atrophy 1-Dependent Mitochondrial Remodeling Controls Steroidogenesis in Trophoblasts 
Current Biology  2012;22(13):1228-1234.
Summary
During human pregnancy, placental trophoblasts differentiate and syncytialize into syncytiotrophoblasts that sustain progesterone production [1]. This process is accompanied by mitochondrial fragmentation and cristae remodeling [2], two facets of mitochondrial apoptosis, whose molecular mechanisms and functional consequences on steroidogenesis are unclear. Here we show that the mitochondria-shaping protein Optic atrophy 1 (Opa1) controls efficiency of steroidogenesis. During syncytialization of trophoblast BeWo cells, levels of the profission mitochondria-shaping protein Drp1 increase, and those of Opa1 and mitofusin (Mfn) decrease, leading to mitochondrial fragmentation and cristae remodeling. Manipulation of the levels of Opa1 reveal an inverse relationship with the efficiency of steroidogenesis in trophoblasts and in mouse embryonic fibroblasts where the mitochondrial steroidogenetic pathway has been engineered. In an in vitro assay, accumulation of cholesterol is facilitated in the inner membrane of isolated mitochondria lacking Opa1. Thus, Opa1-dependent inner membrane remodeling controls efficiency of steroidogenesis.
Graphical Abstract
Highlights
► Mitochondrial remodeling characterize differentiation of human trophoblasts ► Expression of Opa1 decreases during trophoblast differentiation ► Lowered Opa1 increases efficiency of steroidogenesis stimulating cholesterol flux
doi:10.1016/j.cub.2012.04.054
PMCID: PMC3396839  PMID: 22658590
10.  Mitochondrial Dynamics in Cancer and Neurodegenerative and Neuroinflammatory Diseases 
Mitochondria are key organelles in the cell, hosting essential functions, from biosynthetic and metabolic pathways, to oxidative phosphorylation and ATP production, from calcium buffering to red-ox homeostasis and apoptotic signalling pathways. Mitochondria are also dynamic organelles, continuously fusing and dividing, and their localization, size and trafficking are finely regulated. Moreover, in recent decades, alterations in mitochondrial function and dynamics have been implicated in an increasing number of diseases. In this review, we focus on the relationship clarified hitherto between mitochondrial dynamics and cancer, neurodegenerative and neuroinflammatory diseases.
doi:10.1155/2012/729290
PMCID: PMC3391904  PMID: 22792111
11.  Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation 
Human Molecular Genetics  2012;21(17):3858-3870.
The mitochondrial protein AFG3L2 forms homo-oligomeric and hetero-oligomeric complexes with paraplegin in the inner mitochondrial membrane, named m-AAA proteases. These complexes are in charge of quality control of misfolded proteins and participate in the regulation of OPA1 proteolytic cleavage, required for mitochondrial fusion. Mutations in AFG3L2 cause spinocerebellar ataxia type 28 and a complex neurodegenerative syndrome of childhood. In this study, we demonstrated that the loss of AFG3L2 in mouse embryonic fibroblasts (MEFs) reduces mitochondrial Ca2+ uptake capacity. This defect is neither a consequence of global alteration in cellular Ca2+ homeostasis nor of the reduced driving force for Ca2+ internalization within mitochondria, since cytosolic Ca2+ transients and mitochondrial membrane potential remain unaffected. Moreover, experiments in permeabilized cells revealed unaltered mitochondrial Ca2+ uptake speed in Afg3l2−/− cells, indicating the presence of functional Ca2+ uptake machinery. Our results show that the defective Ca2+ handling in Afg3l2−/− cells is caused by fragmentation of the mitochondrial network, secondary to respiratory dysfunction and the consequent processing of OPA1. This leaves a number of mitochondria devoid of connections to the ER and thus without Ca2+ elevations, hampering the proper Ca2+ diffusion along the mitochondrial network. The recovery of mitochondrial fragmentation in Afg3l2−/− MEFs by overexpression of OPA1 rescues the impaired mitochondrial Ca2+ buffering, but fails to restore respiration. By linking mitochondrial morphology and Ca2+ homeostasis, these findings shed new light in the molecular mechanisms underlining neurodegeneration caused by AFG3L2 mutations.
doi:10.1093/hmg/dds214
PMCID: PMC3412383  PMID: 22678058
12.  During autophagy mitochondria elongate, are spared from degradation and sustain cell viability 
Nature cell biology  2011;13(5):589-598.
Summary
A plethora of cellular processes, including apoptosis, depend on regulated changes in mitochondrial shape and ultrastructure. Scarce is our understanding of the role of mitochondria and of their morphology during autophagy, a bulk degradation and recycling process of eukaryotic cells’ constituents. Here we show that mitochondrial morphology determines the cellular response to macroautophagy. When autophagy is triggered, mitochondria elongate in vitro and in vivo. Upon starvation cellular cAMP levels increase and protein kinase A (PKA) becomes activated. PKA in turn phosphorylates the pro-fission dynamin related protein 1 (DRP1) that is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increase dimerization and activity of ATP synthase, and maintain ATP production. When elongation is genetically or pharmacologically blocked, mitochondria conversely consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy.
doi:10.1038/ncb2220
PMCID: PMC3088644  PMID: 21478857
13.  Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli 
EMBO molecular medicine  2010;2(12):490-503.
Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.
doi:10.1002/emmm.201000102
PMCID: PMC3044888  PMID: 21069748
apoptosis; cristae remodelling; fission; Huntington's disease; mitochondria
14.  Two close, too close: Sarcoplasmic reticulum-mitochondrial cross-talk and cardiomyocyte fate 
Circulation research  2010;107(6):689-699.
Mitochondria are key organelles in cell life, whose dysfunction is associated with a variety of diseases. Their crucial role in intermediary metabolism and energy conversion makes them a preferred target in tissues, like the heart, where the energetic demands are very high. In the cardiomyocyte, the spatial organization of mitochondria favors their interaction with the sarcoplasmic reticulum, thereby offering a mechanism for Ca2+mediated crosstalk between these two organelles. Recently, the molecular basis for this interaction has started to be unraveled, and we are learning how ER-mitochondrial interactions are often exploited by death signals, like proapoptotic Bcl-2 family members, to amplify the cell death cascade. Here we will review our current understanding of the structural basis and the functional consequences of the close interaction between sarcoplasmic reticulum and mitochondria on cardiomyocyte function and death.
doi:10.1161/CIRCRESAHA.110.225714
PMCID: PMC2963937  PMID: 20847324
Mitochondrial fusion; endoplasmic reticulum; calcium; bcl2 proteins; apoptosis; mitochondrial permeability transition
15.  Traveling Bax and Forth from Mitochondria to Control Apoptosis 
Cell  2011;145(1):15-17.
Antiapoptotic Bcl-2 proteins on mitochondria inhibit prodeath proteins, such as Bax, which are found primarily in the cytosol. In this issue, Edlich et al., (2011) show that Bax and Bcl-xL interact on the mitochondrial surface and then retrotranslocate to the cytosol, effectively preventing Bax-induced permeabilization of mitochondria.
doi:10.1016/j.cell.2011.03.025
PMCID: PMC3072571  PMID: 21458662
16.  Trichoplein/mitostatin regulates endoplasmic reticulum–mitochondria juxtaposition 
EMBO reports  2010;11(11):854-860.
Trichoplein/mitostatin (TpMs) is a keratin-binding protein that partly colocalizes with mitochondria and is often downregulated in epithelial cancers, but its function remains unclear. In this study, we report that TpMs regulates the tethering between mitochondria and endoplasmic reticulum (ER) in a Mitofusin 2 (Mfn2)-dependent manner. Subcellular fractionation and immunostaining show that TpMs is present at the interface between mitochondria and ER. The expression of TpMs leads to mitochondrial fragmentation and loosens tethering with ER, whereas its silencing has opposite effects. Functionally, the reduced tethering by TpMs inhibits apoptosis by Ca2+-dependent stimuli that require ER–mitochondria juxtaposition. Biochemical and genetic evidence support a model in which TpMs requires Mfn2 to modulate mitochondrial shape and tethering. Thus, TpMs is a new regulator of mitochondria–ER juxtaposition.
doi:10.1038/embor.2010.151
PMCID: PMC2966954  PMID: 20930847
mitochondria; endoplasmic reticulum; trichoplein; mitofusin; apoptosis
17.  Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli 
EMBO Molecular Medicine  2010;2(12):490-503.
Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.
doi:10.1002/emmm.201000102
PMCID: PMC3044888  PMID: 21069748
apoptosis; cristae remodelling; fission; Huntington's disease; mitochondria
19.  Caspase-8 goes cardiolipin: a new platform to provide mitochondria with microdomains of apoptotic signals? 
The Journal of Cell Biology  2008;183(4):579-581.
In certain cell types, apoptosis in response to extracellular stimuli like Fas depends on a mitochondrial amplificatory loop: the apical caspase-8 cleaves and activates the BH3-only member of the Bcl-2 family BID. In turn, BID induces the release of cytochrome c from mitochondria to the cytoplasm, where it is required to fully activate effector caspases. In this issue of The Journal of Cell Biology, Gonzalvez et al. (see p. 681) show that when caspase-8 activation and production of functional BID is required, it is performed on mitochondrial platforms provided by the mitochondrion-specific lipid cardiolipin. Cardiolipin anchors caspase-8 at contact sites between inner and outer mitochondrial membranes, facilitating its self activation. These findings suggests that like other second messengers such as Ca2+ and cAMP, production of apoptotic messengers can be compartmentalized in close proximity to their intracellular target.
doi:10.1083/jcb.200810125
PMCID: PMC2582901  PMID: 19001131
20.  Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function 
EMBO Molecular Medicine  2009;1(2):99-111.
Mutations of the mitochondrial PTEN (phosphatase and tensin homologue)-induced kinase1 (PINK1) are important causes of recessive Parkinson disease (PD). Studies on loss of function and overexpression implicate PINK1 in apoptosis, abnormal mitochondrial morphology, impaired dopamine release and motor deficits. However, the fundamental mechanism underlying these various phenotypes remains to be clarified. Using fruit fly and mouse models we show that PINK1 deficiency or clinical mutations impact on the function of Complex I of the mitochondrial respiratory chain, resulting in mitochondrial depolarization and increased sensitivity to apoptotic stress in mammalian cells and tissues. In Drosophila neurons, PINK1 deficiency affects synaptic function, as the reserve pool of synaptic vesicles is not mobilized during rapid stimulation. The fundamental importance of PINK1 for energy maintenance under increased demand is further corroborated as this deficit can be rescued by adding ATP to the synapse. The clinical relevance of our observations is demonstrated by the fact that human wild type PINK1, but not PINK1 containing clinical mutations, can rescue Complex 1 deficiency. Our work suggests that Complex I deficiency underlies, at least partially, the pathogenesis of this hereditary form of PD. As Complex I dysfunction is also implicated in sporadic PD, a convergence of genetic and environmental causes of PD on a similar mitochondrial molecular mechanism appears to emerge.
doi:10.1002/emmm.200900006
PMCID: PMC3378121  PMID: 20049710
Complex I; mitochondrial dysfunction; Parkinson's disease; reserve pool deficit
21.  Orchestration of lymphocyte chemotaxis by mitochondrial dynamics 
The Journal of Experimental Medicine  2006;203(13):2879-2886.
Lymphocyte traffic is required to maintain homeostasis and perform appropriate immunological reactions. To migrate into inflamed tissues, lymphocytes must acquire spatial and functional asymmetries. Mitochondria are highly dynamic organelles that distribute in the cytoplasm to meet specific cellular needs, but whether this is essential to lymphocyte functions is unknown. We show that mitochondria specifically concentrate at the uropod during lymphocyte migration by a process involving rearrangements of their shape. Mitochondrial fission facilitates relocation of the organelles and promotes lymphocyte chemotaxis, whereas mitochondrial fusion inhibits both processes. Our data substantiate a new role for mitochondrial dynamics and suggest that mitochondria redistribution is required to regulate the motor of migrating cells.
doi:10.1084/jem.20061877
PMCID: PMC2118173  PMID: 17145957
22.  The Mitochondrial Fission Protein hFis1 Requires the Endoplasmic Reticulum Gateway to Induce Apoptosis 
Molecular Biology of the Cell  2006;17(11):4593-4605.
Mitochondrial fission ensures organelle inheritance during cell division and participates in apoptosis. The fission protein hFis1 triggers caspase-dependent cell death, by causing the release of cytochrome c from mitochondria. Here we show that mitochondrial fission induced by hFis1 is genetically distinct from apoptosis. In cells lacking the multidomain proapoptotic Bcl-2 family members Bax and Bak (DKO), hFis1 caused mitochondrial fragmentation but not organelle dysfunction and apoptosis. Similarly, a mutant in the intermembrane region of hFis1-induced fission but not cell death, further dissociating mitochondrial fragmentation from apoptosis induction. Selective correction of the endoplasmic reticulum (ER) defect of DKO cells restored killing by hFis1, indicating that death by hFis1 relies on the ER gateway of apoptosis. Consistently, hFis1 did not directly activate BAX and BAK, but induced Ca2+-dependent mitochondrial dysfunction. Thus, hFis1 is a bifunctional protein that independently regulates mitochondrial fragmentation and ER-mediated apoptosis.
doi:10.1091/mbc.E06-05-0377
PMCID: PMC1635393  PMID: 16914522
23.  Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction 
Journal of Clinical Investigation  2003;112(12):1831-1842.
Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic β cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced β cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on β cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of β cell dysfunction and type 2 diabetes.
doi:10.1172/JCI200319774
PMCID: PMC297000  PMID: 14679178
24.  Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli 
EMBO Molecular Medicine  2010;2(12):490-503.
Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis.
doi:10.1002/emmm.201000102
PMCID: PMC3044888  PMID: 21069748
apoptosis; cristae remodelling; fission; Huntington's disease; mitochondria

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