Date of Award

Summer 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

First Advisor

Stuart, Rosemary

Second Advisor

Manogatan, Anita

Third Advisor

Yang, Pinfen

Abstract

Oxidative phosphorylation (OXPHOS) is responsible for the generation of most of the cellular energy (ATP) within the cell. OXPHOS enzymes are mosaic in origin, as protein subunits are encoded by both nuclear and mitochondrial genomes. Mitochondrial ribosomes have been shown to respond to the availability and import of nuclearly encoded OXPHOS components, and thus the current dogma states that mitochondrial translation is synchronized to the import of these nuclear encoded proteins, as well as the availability of chaperones to co-assemble them within the inner mitochondrial membrane. We demonstrate here that the yeast Mrp7 (bL27) protein is involved in the coordination between mitochondrial protein synthesis and OXPHOS enzyme assembly, through key domains at both its N- and C-terminus, and those domains are required for optimal OXPHOS function. Additionally, we show that mitoribosomal protein synthesis occurs at high levels during glycolysis fermentation and in a manner uncoupled from OXPHOS complex assembly regulation. Furthermore, we provide evidence that the mitospecific domain of Mrp7 (bL27), a mitoribosomal component, is required to maintain mitochondrial protein synthesis during fermentation but is not required under respiration growth conditions. Maintaining mitochondrial translation under high-glucose-fermentation conditions also involves Mam33 (p32/gC1qR homologue), a binding partner of Mrp7's mitospecific domain, and together they confer a competitive advantage for a cell's ability to adapt to respiration-based metabolism when glucose becomes limiting. Furthermore, our findings support that the mitoribosome, and specifically the central protuberance region, may be differentially regulated and/or assembled, under the different metabolic conditions of fermentation and respiration. On the basis of our findings, we propose that the purpose of mitochondrial translation is not limited to the assembly of OXPHOS complexes, but also plays a role in mitochondrial signaling critical for switching cellular metabolism from a glycolysis- to a respiration-based state.

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