Student Theses and Dissertations

Date of Award

2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Tavazoie Laboratory

Abstract

Balancing metabolic demands with transcriptional output requires efficient communication between mitochondria and the nucleus. However, the mitochondrial factors that mediate signals to the nucleus remain poorly defined. In eukaryotes, the mitochondrial genome encodes transfer RNAs (mito-tRNAs) that function in mitochondrial-specific translation. Here, we report the detection of multiple mito-tRNAs within the nucleus of human cells. Focused studies of one such nuclear-transported mito-tRNA-asparagine (mito-tRNA-Asn) revealed that its cognate charging enzyme (NARS2) is also present in the nucleus. Nuclear localization of mito-tRNA-Asn and NARS2 was dependent on the VDAC1 mitochondrial channel and importin-α nuclear transport factor, respectively. Mito-tRNA-Asn promoted the interaction of NARS2 with histone deacetylase 2 (HDAC2) and repressed HDAC2 association with chromatin. Accordingly, inhibiting tRNA-dependent NARS2-HDAC2 complex formation licensed HDAC2 binding to target gene loci and elicited transcriptional silencing. Interfering with the mito-tRNA-Asn/NARS2/HDAC2 axis elicited metabolomic alterations in glycolytic and TCA intermediates, amino acids, and nucleotide biosynthesis. Importantly, mitotRNA- dependent transcriptional repression of glutaminase diverted glutamine towards the synthesis and maintenance of nucleotide pools, and enhanced cancer cell growth. These findings uncover nucleic-acid mediated communication between two organelles and the existence of a machinery for nuclear gene control by a mito-tRNA that restricts growth through metabolic control.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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