Deafness-associated mitochondrial 12S rRNA mutation reshapes mitochondrial and cellular homeostasis
Yunfan He1, Zhining Tang2, Gao Zhu3
1Center for Mitochondrial Biomedicine and Department of Otolaryngology-Head and Neck Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China; Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China; Center for Genetic Medicine, Zhejiang University International Institute of Medicine, Yiwu, Zhejiang, China.
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.
Insights
The m.1555A>G mutation in human mitochondrial 12S ribosomal RNA disrupts cellular energy production and mitochondrial health, leading to deafness. This study reveals how these defects trigger cellular repair mechanisms, impacting homeostasis.
Area of Science:
- Mitochondrial Biology
- Genetics
- Cellular Physiology
Background:
- The m.1555A>G mutation in human mitochondrial 12S ribosomal RNA is a known cause of aminoglycoside-induced and non-syndromic deafness.
- Previous studies linked this mutation to impaired mitochondrial translation and oxidative phosphorylation (OXPHOS).
- Mechanisms underlying mitochondrial dysfunction and cellular integrity regulation in response to this mutation were poorly understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which the m.1555A>G mutation impacts mitochondrial function and cellular homeostasis.
- To investigate the cellular signaling pathways involved in maintaining mitochondrial and cellular integrity under mutation-induced stress.
Main Methods:
- Utilized cybrid cell lines derived from a hearing-impaired subject with the m.1555A>G mutation and a hearing normal control.
- Analyzed the expression of nucleus-encoded subunits and assembly factors for OXPHOS complexes.
- Assessed mitochondrial function, including membrane potential, reactive oxygen species (ROS) production, oxygen consumption, and ATP synthesis.
Main Results:
- The m.1555A>G mutation led to downregulated nucleus-encoded OXPHOS subunits (Complexes I, IV) and upregulated assembly factors.
- Observed aberrant assembly, instability, and reduced activity of OXPHOS complexes (I, IV, V), decreased oxygen consumption, and diminished ATP production.
- Mutant cells showed decreased membrane potential, increased ROS, imbalanced mitochondrial dynamics (increased fission), impaired mitophagy, and upregulated mitophagy pathways (Parkin, Pink, BNIP3, NIX).
Conclusions:
- The m.1555A>G mutation disrupts mitochondrial biogenesis and function, leading to cellular stress and impaired mitochondrial quality control.
- Cells activate both ubiquitin-dependent and independent mitophagy pathways in response to mitochondrial defects.
- The study provides insights into the pathophysiology of mitochondrial deafness by highlighting the reshaping of cellular homeostasis due to the 12S rRNA 1555A>G mutation.
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