Abstract
The replicative lifespan of the yeast Saccharomyces cerevisiae models the aging of stem cells. Age asymmetry between the mother and daughter cells is established during each cell division, such that the daughter retains the capacity for self-renewal while this ability is diminished in the mother. The segregation of fully-functional mitochondria to daughter cells is one mechanism that underlies this age asymmetry. In this study, we have examined the role of mitochondrial dynamics in this phenomenon. Mitochondrial dynamics involve the processes of fission and fusion. Out of the three fusion and three fission genes tested, we have found that only FZO1 is required for the segregation of fully-functional mitochondria to daughter cells and in the maintenance of age asymmetry as manifested in the potential of daughters for a full replicative lifespan despite its deterioration in their mothers. The quality of mitochondria is determined by their turnover, and we have also discovered that deletion of FZO1 reduces mitophagy. Mitochondrial dysfunction elicits a compensatory retrograde response that extends replicative lifespan. Typically, the dysfunction that triggers this response encompasses energy production. The disruption of mitochondrial dynamics by deletion of FZO1 also activates the retrograde response to extend replicative lifespan. We call this novel pathway the mitochondrial dynamics-associated retrograde response (MDARR) because it is distinct in the signal proximal to the mitochondrion that initiates it. Furthermore, the MDARR engages the mitophagy receptor Atg32 on the mitochondrial surface, and we propose that this is due to the accumulation of Atg32-Atg11-Dnm1 complexes on the mitochondrion in the absence of Fzo1 activity. MDARR can be masked by the operation of the ‘classic’ retrograde response.
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Acknowledgements
We are grateful to Rodney J. Devenish for the gift of pAS1NB::mt-Rosella. We thank Jennifer Wyckoff for DNA sequencing and for assistance with microscopy, which were carried out in the Genomics, Biostatistics, and Bioinformatics Core, supported by Grant P20GM103629 from the National Institutes of Health (NIH). This research was supported by Grant AG006168 from the NIH.
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Jiang, J.C., Stumpferl, S.W. & Jazwinski, S.M. Dual roles of mitochondrial fusion gene FZO1 in yeast age asymmetry and in longevity mediated by a novel ATG32-dependent retrograde response. Biogerontology 20, 93–107 (2019). https://doi.org/10.1007/s10522-018-9779-z
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DOI: https://doi.org/10.1007/s10522-018-9779-z