Defining the links between perturbed… (F32AG105031) – Project Grant to The Regents Of The University Of…

Abstract: Mitochondria are biosynthetic signaling hubs core to human health, and their dysfunction has long been associated with aging and development of age-related diseases. Often observed in aging and disease is disrupted mitochondrial mass homeostasis (i.e., an inappropriate accumulation or loss of mitochondria). Despite this, the direct consequences of disrupted mitochondrial mass on aging and other fundamental cellular processes remain poorly understood. The overall goal of this application is to delineate how cells and animals sense, react to, and absolve states of aberrant mitochondrial mass. The rationale is that in normal aging and in age-related disease, such as parkinson's disease and sarcopenia, the amount of mitochondria present within tissues becomes dysregulated. Thus, IT is paramount to understand how changes to mitochondrial mass impacts cellular homeostasis both in normal physiological and aging contexts. A major barrier to our understanding in this regard is the lack of tools to precisely and directly modulate mitochondrial mass. This proposal has the following specific aims: 1) determine how a state of reduced mitochondrial mass affects cellular function and age-related cell phenotypes; 2) identify genes involved in restoring mitochondrial mass homeostasis and how this process differs across tissues and age. This proposed application is innovative because 1) IT uses a new strategy to precisely modulate mitochondrial mass, providing a unique angle to decipher the relationship between mitochondrial mass aberrations and aging, and 2) IT will uncover regulators of mitochondrial mass homeostasis and how this differs between tissues in the multi-tissue aging organism c elegans. Previous work has used stress-induced mitochondrial dysfunction or genetic mutants of endogenous mitochondrial quality control proteins to generate changes in mitochondrial mass. While enlightening, these methods only alter mitochondrial mass by indirect means and thus make deconvolving consequences of mitochondrial dysfunction from changes to mitochondrial mass difficult. The research in this proposal is significant because by clarifying the relationships between mitochondrial mass, cell function, and aging, we will further our understanding of a fundamental aspect of organismal health. In addition, by identifying regulators of mitochondrial mass homeostasis, this proposal will uncover therapeutic targets for correcting dysregulated mitochondrial mass that manifests in human disease and aging. Along with the proposed research, this application also offers a fellowship training plan that will catalyze DR. Schmitz's personal and career development. His goal is to become an adept independent academic investigator. To help him achieve this goal, this award will provide DR. Schmitz with the opportunity to improve his scientific writing and communications skills, hone his mentoring ability, and become an expert in the field of aging. This will be further fostered by the excellent research culture present at UC berkeley and DR. Andrew dillin's lab.

Defining the links between perturbed mitochondrial mass homeostasis and aging

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