Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis

Yunfan He; Gao Zhu; Xincheng Li; Mi Zhou; Min-Xin Guan

doi:10.1016/j.isci.2024.108883

Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis

iScience. 2024 Jan 12;27(2):108883. doi: 10.1016/j.isci.2024.108883. eCollection 2024 Feb 16.

Authors

Yunfan He^{1

2

3}, Gao Zhu^{1

2

3

4}, Xincheng Li², Mi Zhou², Min-Xin Guan^{1

2

3

4

5}

Affiliations

¹ Center for Mitochondrial Biomedicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
² Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, Zhejiang, China.
³ Center for Genetic Medicine, Zhejiang University International Institute of Medicine, Yiwu, Zhejiang, China.
⁴ Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, Zhejiang, China.
⁵ Key Lab of Reproductive Genetics, Ministry of Education of PRC, Zhejiang University, Hangzhou, Zhejiang, China.

Abstract

Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNA^Met 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.

Keywords: Cell biology; Molecular physiology; Properties of biomolecules.