# Mitochondrial inheritance and quality control

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $489,973

## Abstract

Asymmetric cell division, the process whereby asymmetric inheritance of cellular components gives rise to two
daughter cells that have different characteristics and fates, is essential for development. It is also essential for
maintaining stem and progenitor cells, which are critical for tissue and organ renewal and for the lifespan of the
organism. We use the budding yeast, Saccharomyces cerevisiae, to study asymmetric cell division and the role
of that process in lifespan control. One consequence of asymmetric cell division in S. cerevisiae is mother-
daughter age asymmetry, the phenomenon whereby daughter cells or buds are born young, largely
independent of the age of their mother cells. We find that mitochondria, established aging determinants, are
asymmetrically inherited during yeast cell division. Yeast daughter cells inherit higher-functioning mitochondria,
which are more reduced, have higher membrane potential and contain lower levels of reactive oxygen species.
We find that the membrane-cytoskeleton interactions that drive mitochondrial movement in budding yeast
result in preferential transport of higher-functioning mitochondria from mother to daughter cell. Moreover, we
identified components of the tethering machineries that anchor and retain higher-functioning mitochondria in
mother and daughter cells. Interestingly, we find that the tether for fitter mitochondria in mother cells responds
to previously unappreciated polarity cues and identified a role for the actin cytoskeleton in region-specific
localization of the anchor and/or polarity cues. Equally important, we find that promoting inheritance of fitter
mitochondria by yeast daughter cells can extend lifespan and promote healthspan (quality of life in advanced
age). We will study 1) the polarity cues, its regulators, and new components of the anchorage machinery, 2)
the mechanism underlying cytoskeleton-dependent localization of the polarity factor or its regulators to
mitochondrial anchorage sites, and 3) the role of the polarity factor, its regulators, and its targets in lifespan
control. In complementary studies, we identified a major role for the mitochondria-associated degradation
pathway (MAD) in mitochondrial quality control in response to mild oxidative stress in the organelle. MAD is
poorly understood. However, it is similar to ERAD, a pathway that recognizes unfolded ER proteins and
retrotranslocates them to the surface of the organelle, where they are ubiquitinated and degraded by the
proteasome. We will study 1) MAD targets and components within mitochondria, 2) the mechanism of action of
MAD components, and 3) the role of MAD in mitochondrial quality control and lifespan control. Although
asymmetric inheritance has been studied almost exclusively during development, recent evidence indicates
that mitochondria are asymmetrically inherited in human mammary stem-like cells and that this process affects
cell fate. Moreover, deletion of a MAD component results in fatal mit...

## Key facts

- **NIH application ID:** 10135105
- **Project number:** 5R35GM122589-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Liza A Pon
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $489,973
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135105

## Citation

> US National Institutes of Health, RePORTER application 10135105, Mitochondrial inheritance and quality control (5R35GM122589-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135105. Licensed CC0.

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