Unopposed mitochondrial fission leads to severe lifespan shortening

Scheckhuber, Christian Q.; Wanger, Ruth Anna; Mignat, Cora A.; Osiewacz, Heinz D.

doi:10.4161/cc.10.18.17196

Cited by 42 publications

(28 citation statements)

References 41 publications

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“…5A), indicating that impaired mitochondrial fusion accelerated aging. This was in agreement with the observation in S. cerevisiae that the absence of the OPA1/Msp1 homolog Mgm1 reduced lifespan (Scheckhuber et al, 2011). Importantly, treatment with PGJ 2 resulted in increased lifespan of wt and msp1Δ cells, whereas the CLS of dnm1Δ cells was unchanged by PGJ 2 (Fig.…”

Section: Prostaglandin J 2 Uncovers a Role For Mitochondrial Fission supporting

confidence: 90%

Chemical genetic screen in fission yeast reveals roles for vacuolar acidification, mitochondrial fission, and cellular GMP levels in lifespan extension

2013

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The discovery that genetic mutations in several cellular pathways can increase lifespan has lent support to the notion that pharmacological inhibition of aging pathways can be used to extend lifespan and to slow the onset of age-related diseases. However, so far, only few compounds with such activities have been described. Here, we have conducted a chemical genetic screen for compounds that cause the extension of chronological lifespan of Schizosaccharomyces pombe. We have characterized eight natural products with such activities, which has allowed us to uncover so far unknown anti-aging pathways in S. pombe. The ionophores monensin and nigericin extended lifespan by affecting vacuolar acidification, and this effect depended on the presence of the vacuolar ATPase (V-ATPase) subunits Vma1 and Vma3. Furthermore, prostaglandin J₂ displayed anti-aging properties due to the inhibition of mitochondrial fission, and its effect on longevity required the mitochondrial fission protein Dnm1 as well as the G-protein-coupled glucose receptor Git3. Also, two compounds that inhibit guanosine monophosphate (GMP) synthesis, mycophenolic acid (MPA) and acivicin, caused lifespan extension, indicating that an imbalance in guanine nucleotide levels impinges upon longevity. We furthermore have identified diindolylmethane (DIM), tschimganine, and the compound mixture mangosteen as inhibiting aging. Taken together, these results reveal unanticipated anti-aging activities for several phytochemicals and open up opportunities for the development of novel anti-aging therapies.

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Section: Prostaglandin J 2 Uncovers a Role For Mitochondrial Fission supporting

confidence: 90%

Chemical genetic screen in fission yeast reveals roles for vacuolar acidification, mitochondrial fission, and cellular GMP levels in lifespan extension

2013

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“…In P. anserina and yeast knockout mutants lacking the mitochondrial dynaminlike protein Dnm1 that promotes fission, fragmentation of the mitochondrial network is delayed, which in P. anserina results in a ninefold longer life span (11). Conversely, yeast strains lacking the dynamin-like fusion protein Mgm1 [mitochondrial genome maintenance 1; corresponding to OPA1 (optic atrophy 1) in mammals] are incapable of mitochondrial fusion and have a reduced replicative and chronological life span (22).…”

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confidence: 99%

Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria

Daum

Walter

Horst

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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203

183

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Aging is one of the most fundamental, yet least understood biological processes that affect all forms of eukaryotic life. Mitochondria are intimately involved in aging, but the underlying molecular mechanisms are largely unknown. Electron cryotomography of whole mitochondria from the aging model organism Podospora anserina revealed profound age-dependent changes in membrane architecture. With increasing age, the typical cristae disappear and the inner membrane vesiculates. The ATP synthase dimers that form rows at the cristae tips dissociate into monomers in inner-membrane vesicles, and the membrane curvature at the ATP synthase inverts. Dissociation of the ATP synthase dimer may involve the peptidyl prolyl isomerase cyclophilin D. Finally, the outer membrane ruptures near large contact-site complexes, releasing apoptogens into the cytoplasm. Inner-membrane vesiculation and dissociation of ATP synthase dimers would impair the ability of mitochondria to supply the cell with sufficient ATP to maintain essential cellular functions.subtomogram averaging | cell death

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“…Conversely, overexpression of PaDNM1 in P. anserina shortens the life span (30). In yeast, ⌬mgm1 and ⌬fzo1 mutants, which exhibit abnormal mitochondrial fusion, have a shortened life span (31,32). Taken together, these findings suggest that aging is associated with mitochondrial fragmentation.…”

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confidence: 48%

A uvs-5 Strain Is Deficient for a Mitofusin Gene Homologue, fzo1 , Involved in Maintenance of Long Life Span in Neurospora crassa

et al. 2013

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Mitochondria are highly dynamic organelles that continuously fuse and divide. To maintain mitochondria, cells establish an equilibrium of fusion and fission events, which are mediated by dynamin-like GTPases. We previously showed that an mus-10 strain, a mutagen-sensitive strain of the filamentous fungus Neurospora crassa, is defective in an F-box protein that is essential for the maintenance of mitochondrial DNA (mtDNA), long life span, and mitochondrial morphology. Similarly, a uvs-5 mutant accumulates deletions within its mtDNA, has a shortened life span, and harbors fragmented mitochondria, the latter of which is indicative of an imbalance between mitochondrial fission and fusion. Since the uvs-5 mutation maps very close to the locus of fzo1, encoding a mitofusin homologue thought to mediate mitochondrial outer membrane fusion, we determined the sequence of the fzo1 gene in the uvs-5 mutant. A single amino acid substitution (Q368R) was found in the GTPase domain of the FZO1 protein. Expression of wild-type FZO1 in the uvs-5 strain rescued the mutant phenotypes, while expression of a mutant FZO1 protein did not. Moreover, when knock-in of the Q368R mutation was performed on a wild-type strain, the resulting mutant displayed phenotypes identical to those of the uvs-5 mutant. Therefore, we concluded that the previously unidentified uvs-5 gene is fzo1. Furthermore, we used immunoprecipitation analysis to show that the FZO1 protein interacts with MUS-10, which suggests that these two proteins may function together to maintain mitochondrial morphology.

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Unopposed mitochondrial fission leads to severe lifespan shortening

Cited by 42 publications

References 41 publications

Chemical genetic screen in fission yeast reveals roles for vacuolar acidification, mitochondrial fission, and cellular GMP levels in lifespan extension

Chemical genetic screen in fission yeast reveals roles for vacuolar acidification, mitochondrial fission, and cellular GMP levels in lifespan extension

Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria

A uvs-5 Strain Is Deficient for a Mitofusin Gene Homologue, fzo1 , Involved in Maintenance of Long Life Span in Neurospora crassa

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