Abstract

Mitochondria, popularly nicknamed as “powerhouses of the cell,” are central to not only cellular energy production but also processes such as amino acids and heme biosynthesis, reactive oxygen species production and signaling, and apoptotic regulation. Thus, a healthy and functional mitochondrial population is crucial to maintain cell function, and mechanisms have emerged to serve as quality and population control for mitochondria to ensure the overall health of the organelle. Here, we show that PPTC7, a mitochondrial phosphatase, is a key player for mitochondrial quality control. We previously found that germline knockout of Pptc7 (Pptc7-/-) causes mice to experience hypoketotic hypoglycemia with lactic acidosis, indicative of inborn errors of metabolism, and eventually leads perinatal lethality with complete penetrance. We therefore aimed to understand the biological functions of PPTC7 to explain the phenotypes we have observed in Pptc7-/- mice. We found that the knockout of PPTC7 (PPTC7 KO) causes an increase in the mitophagy receptors BNIP3 and NIX, an increase in mitophagic flux, and a decrease in the levels of most mitochondrial proteins. Despite these robust phenotypes, the mechanisms linking BNIP3 and PPTC7 were unclear, as PPTC7 was known only to reside within the mitochondrial matrix, whereas mitophagy is regulated at the outer mitochondrial membrane (OMM). We discovered that PPTC7 is dually localized at both the OMM and in the matrix, and that OMM-localized PPTC7 proximally and dynamically interacts with BNIP3 and NIX to facilitate their proteasomal degradation, thereby controlling mitophagic flux. To understand the mechanisms underlying this dual targeting, we found that PPTC7 contains an evolutionarily gained glycine-rich N-terminal domain directly following its mitochondrial transit sequence that is necessary for its OMM-localization, as deletion of this polyglycine tract directs PPTC7 solely in the matrix. Our findings have both illuminated the functions of OMM-localized PPTC7 and created tools to study the functions of matrix-localized PPTC7. Collectively, our findings suggest that PPTC7 facilitates mitochondrial protein homeostasis and quality control by controlling the proteasomal degradation of the mitophagy receptors BNIP3 and NIX to tightly control mitochondrial populations and ensure cellular and organismal health.

Committee Chair

Natalie Niemi

Committee Members

Benjamin Garcia; David Kast; Kyle McCommis; Rajan Sah

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Biochemistry)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

3-26-2026

Language

English (en)

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Available for download on Friday, March 24, 2028

Included in

Biochemistry Commons

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