期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 72, 期 13, 页码 2585-2598出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-015-1863-9
关键词
Tfam; Rho0; Photoactivation; Mfn1; Mfn2; Nucleoids
资金
- 'Strategic Priority Research Program' of the Chinese Academy of Sciences [XDA01020108]
- Ministry of Science and Technology 973 program [2013CB967403, 2012CB721105]
- Ministry of Science and Technology 863 Program [2012AA02A708]
- National Natural Science Foundation projects of China [31271527]
- International Cooperation Project of Guangdong Science and Technology Program [2012B050300022]
- Guangzhou Science and Technology Program [2014Y2-00161]
- Guangdong Natural Science Foundation for Distinguished Young Scientists [S20120011368]
- Chinese Academy of Sciences
Heteroplasmic cells, harboring both mutant and normal mitochondrial DNAs (mtDNAs), must accumulate mutations to a threshold level before respiratory activity is affected. This phenomenon has led to the hypothesis of mtDNA complementation by inter-mitochondrial content mixing. The precise mechanisms of heteroplasmic complementation are unknown, but it depends both on the mtDNA nucleoid dynamics among mitochondria as well as the mitochondrial dynamics as influenced by mtDNA. We tracked nucleoids among the mitochondria in real time to show that they are shared after complete fusion but not 'kiss-and-run'. Employing a cell hybrid model, we further show that mtDNA-less mitochondria, which have little ATP production and extensive Opa1 proteolytic cleavage, exhibit weak fusion activity among themselves, yet remain competent in fusing with healthy mitochondria in a mitofusin- and OPA1-dependent manner, resulting in restoration of metabolic function. Depletion of mtDNA by overexpression of the matrix-targeted nuclease UL12.5 resulted in heterogeneous mitochondrial membrane potential (Delta Im) at the organelle level in mitofusin-null cells but not in wild type. In this system, overexpression of mitofusins or application of the fusion-promoting drug M1 could partially rescue the metabolic damage caused by UL12.5. Interestingly, mtDNA transcription/translation is not required for normal mitochondria to restore metabolic function to mtDNA-less mitochondria by fusion. Thus, interplay between mtDNA and fusion capacity governs a novel 'initial metabolic complementation'.
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