Why you want your mitochondria to fuse

[Guest guest]

So, your mitochondria are constantly dividing and fusing. Which would you prefer?

The correct answer is fusing. When they "fuse", your cells are protected against apoptosis. When they are "fissioning", then your cells are more prone to apoptosis.

The relationship between apoptosis and aging is just as strong, if not stronger, than that between "radicals" and aging. In the cells you want to keep, the prevention of apoptosis is of the upmost importance.

There is a CR-related ways that may be operating here. For one thing, it has been noted that caloric restriction leads to the activation of PGC-1alpha, which is a gene known to activate "mitofusin" proteins, which as their name implies coordinate mitochondrial fusion. In fact, the SIRT1 "sirtuin" protein interacts with PGC-1alpha, which itself may be coordinating mitochondrial fusion through the mitofusin proteins. This specfic deterministic sequence has not been experimentally validated in its totality, but the confidence that I have that this is operating is fairly high.

Even if that lead does not pan out, it has already been shown that obesity itself can lead to depressed Mfn2 function, which stands for "Mitofusin 2", a protein that helps fuse these guys. Interestingly, this exact same hypofunctionality in Mfn2 has been correlated to mitochondria-mediated apoptosis.

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J Biol Chem. 2003 May 9;278(19):17190-7. Epub 2003 Feb 21.

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Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity.Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacin M, Vidal H, F, Brand M, Zorzano A.Parc Cientific de Barcelona, Facultat de Biologia, Universitat de Barcelona, Barcelona 08028, Spain.In many cells and specially in muscle, mitochondria form elongated filaments or a branched reticulum. We show that Mfn2 (mitofusin 2), a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, is induced during myogenesis and contributes to the maintenance and operation of the mitochondrial network. Repression of

Mfn2 caused morphological and functional fragmentation of the mitochondrial network into independent clusters. Concomitantly, repression of Mfn2 reduced glucose oxidation, mitochondrial membrane potential, cell respiration, and mitochondrial proton leak. We also show that the Mfn2-dependent mechanism of mitochondrial control is disturbed in obesity by reduced Mfn2 expression. In all, our data indicate that Mfn2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced Mfn2 expression may explain some of the metabolic alterations associated with obesity.PMID: 12598526 [PubMed - indexed for MEDLINE]

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J Biol Chem. 2005 Jul 15;280(28):26185-92. Epub 2005 May 17.

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Disruption of fusion results in mitochondrial heterogeneity and dysfunction.Chen H, Chomyn A, Chan DC.Division of Biology, California Institute of Technology, Pasadena, California 91125.Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion

and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and Mfn2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzoDelta yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.PMID: 15899901 [PubMed - in process]

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Nature. 2005 Mar 3;434(7029):113-8.

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Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P.Department of Cell Biology, s Hopkins University School of Medicine,

Baltimore, land 21205, USA.Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of

PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.PMID: 15744310 [PubMed - indexed for MEDLINE]

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Physiol. 2005 Jun 16; [Epub ahead of print]

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Mitofusins 1/2 and ERR{alpha} expression are increased in human skeletal muscle after physical exercise.Cartoni R, Leger B, Hock MB, Praz M, Crettenand A, Pich S, Ziltener JL, Luthi F, Deriaz O, Zorzano A, Gobelet C, Kralli A, AP.Clinique Romande de Readaptation SUVA Care.Mitochondrial impairment is hypothesized to contribute to the pathogenesis of insulin resistance. Mitofusin (Mfn) proteins regulate the biogenesis and maintenance of the mitochondrial network, and when inactivated, cause a failure in the mitochondrial architecture and decreases in oxidative capacity and glucose oxidation. Exercise increases muscle mitochondrial content, size, oxidative capacity and aerobic

glucose oxidation. To address if Mfn proteins are implicated in these exercise-induced responses, we measured Mfn1 and Mfn2 mRNA levels, pre-, post-, 2 and 24 hours post-exercise. Additionally, we measured the expression levels of transcriptional regulators that control mitochondrial biogenesis and functions, including PGC-1alpha, NRF-1, NRF-2 and the recently implicated ERRalpha. We show that Mfn1, Mfn2, NRF-2 and COX IV mRNA were increased 24 hours post-exercise, while PGC-1alpha and ERRalpha mRNA increased 2 hours post-exercise. Finally, using in vitro cellular assays, we demonstrate that Mfn2 gene expression is driven by a PGC-1alpha program dependent on ERRalpha. The PGC-1alpha/ERRalpha-mediated induction of Mfn2 suggests a role of these two factors in mitochondrial fusion. Our results provide evidence that PGC-1alpha not only mediates the increased expression of oxidative phosphorylation genes but

also mediates alterations in mitochondrial architecture in response to aerobic exercise in humans.PMID: 15961417 [PubMed - as supplied by publisher]

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J Biol Chem. 2005 Jul 1;280(26):25060-70. Epub 2005 May 4.

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Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization.Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H.University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7,

Canada.Mitochondrial fusion in higher eukaryotes requires at least two essential GTPases, Mitofusin 1 and Mitofusin 2 (Mfn2). We have created an activated mutant of Mfn2, which shows increased rates of nucleotide exchange and decreased rates of hydrolysis relative to wild type Mfn2. Mitochondrial fusion is stimulated dramatically within heterokaryons expressing this mutant, demonstrating that hydrolysis is not requisite for the fusion event, and supporting a role for Mfn2 as a signaling GTPase. Although steady-state mitochondrial fusion required the conserved intermembrane space tryptophan residue, this requirement was overcome within the context of the hydrolysis-deficient mutant. Furthermore, the punctate localization of Mfn2 is lost in the dominant active mutants, indicating that these sites are functionally controlled by changes in the nucleotide state of Mfn2. Upon staurosporine-stimulated

cell death, activated Bax is recruited to the Mfn2-containing puncta; however, Bax activation and cytochrome c release are inhibited in the presence of the dominant active mutants of Mfn2. The dominant active form of Mfn2 also protected the mitochondria against free radical-induced permeability transition. In contrast to staurosporine-induced outer membrane permeability transition, pore opening induced through the introduction of free radicals was dependent upon the conserved intermembrane space residue. This is the first evidence that Mfn2 is a signaling GTPase regulating mitochondrial fusion and that the nucleotide-dependent activation of Mfn2 concomitantly protects the organelle from permeability transition. The data provide new insights into the critical relationship between mitochondrial membrane dynamics and programmed cell death.PMID: 15878861 [PubMed - in process]

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J Biol Chem. 2004 Dec 10;279(50):52726-34. Epub 2004 Sep 30.

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Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis.Sugioka R, Shimizu S, Tsujimoto Y.Laboratory of Molecular Genetics, Department of Post-Genomics & Diseases, Osaka University Medical School, and Solution-Oriented Research for Science and Technology of Japan Science and Technology Corporation, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.Mitochondrial morphology and physiology are regulated by the processes of fusion and fission. Some forms of apoptosis are reported to be associated with mitochondrial fragmentation. We showed that overexpression of Fzo1A/B (rat) proteins involved in mitochondrial fusion, or silencing of Dnm1 (rat)/Drp1 (human) (a mitochondrial fission protein),

increased elongated mitochondria in healthy cells. After apoptotic stimulation, these interventions inhibited mitochondrial fragmentation and cell death, suggesting that a process involved in mitochondrial fusion/fission might play a role in the regulation of apoptosis. Consistently, silencing of Fzo1A/B or Mfn1/2 (a human homolog of Fzo1A/B) led to an increase of shorter mitochondria and enhanced apoptotic death. Overexpression of Fzo1 inhibited cytochrome c release and activation of Bax/Bak, as assessed from conformational changes and oligomerization. Silencing of Mfn or Drp1 caused an increase or decrease of mitochondrial sensitivity to apoptotic stimulation, respectively. These results indicate that some of the proteins involved in mitochondrial fusion/fission modulate apoptotic cell death at the mitochondrial level.PMID: 15459195 [PubMed - indexed for MEDLINE]

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Science. 2005 Jul 15;309(5733):481-4.

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Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA.Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation

of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.PMID: 16020738 [PubMed - in process]

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