Deafness-associated Mitochondrial 12S RRNA Mutation Reshapes Mitochondrial and Cellular Homeostasis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2024 Dec 24

PMID 39716492

Authors

Yunfan He

Zhining Tang

Gao Zhu

Luhang Cai

Chao Chen

Min-Xin Guan

Affiliations

Soon will be listed here.

Abstract

Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS). However, the mechanisms by which mitochondrial dysfunctions induced by m.1555A>G mutation regulate intracellular signaling for mitochondrial and cellular integrity remain poorly understood. Here, we demonstrated that the m.1555A>G mutation downregulated the expression of nucleus-encoded subunits of complexes I and IV but upregulated the expression of assemble factors for OXPHOS complexes, using cybrids derived from one hearing-impaired Chinese subject bearing the m.1555A>G mutation and from one hearing normal control lacking the mutation. These alterations resulted in the aberrant assembly, instability, and reduced activities of respiratory chain enzyme complexes I, IV, and V, rate of oxygen consumption, and diminished ATP production. Furthermore, the mutant cell lines carrying the m.1555A>G mutation exhibited decreased membrane potential and increased the production of reactive oxygen species. The aberrant assembly and biogenesis of OXPHOS impacted mitochondrial quality controls, including the imbalance of mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology and impaired mitophagy. Strikingly, the cells bearing the m.1555A>G mutation revealed the upregulation of both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing levels of Parkin, Pink, BNIP3 and NIX, respectively. The m.1555A>G mutation-induced deficiencies ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into pathophysiology of mitochondrial deafness arising from reshaping mitochondrial and cellular homeostasis due to 12S rRNA 1555A>G mutation.

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