澳大利亚昆士兰大学Steven Zuryn课题组发现，线粒体6mA修饰的失调促进突变mtDNA的扩增并导致秀丽隐杆线虫衰老。相关论文于2024年8月21日在线发表在《细胞—代谢》杂志上。

研究人员表示，在几乎所有真核生物中，线粒体DNA（mtDNA）编码氧化磷酸化（OXPHOS）所需的蛋白质以及其合成所需的RNA。虽然调控mtDNA拷贝数和表达的机制尚未完全理解，但它们对于确保核编码和mtDNA编码亚基正确比例的OXPHOS复合物的组装至关重要。

研究人员检测到多种动物和植物物种的mtDNA上存在腺苷N6-甲基化（6mA）。在秀丽隐杆线虫（C. elegans）中，这种修饰由DNA甲基转移酶DAMT-1和去甲基化酶ALKB-1调控。通过针对性地调节这些酶的活性，mtDNA 6mA修饰的失调会异常改变mtDNA拷贝数和转录水平，损害OXPHOS功能，增加氧化应激，并缩短寿命。此外，mtDNA 6mA低甲基化还会促进有害mtDNA跨代传播。这些结果共同揭示了mtDNA 6mA在真核生物中高度保守，并通过影响mtDNA拷贝数、表达和体内可遗传突变水平来调节寿命。

附：英文原文

Title: Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans

Author: Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M. Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn

Issue&Volume: 2024-08-21

Abstract: In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessaryfor oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. Themechanisms of regulation of mtDNA copy number and expression are not completely understoodbut crucially ensure the correct stoichiometric assembly of OXPHOS complexes fromnuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA)on the mtDNA of diverse animal and plant species. This modification is regulated inC. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA6mA through targeted modulation of these activities inappropriately alters mtDNA copynumber and transcript levels, impairing OXPHOS function, elevating oxidative stress,and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotesthe cross-generational propagation of a deleterious mtDNA. Together, these resultsreveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespanby influencing mtDNA copy number, expression, and heritable mutation levels in vivo.

DOI: 10.1016/j.cmet.2024.07.020

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00291-2