title: Mitochondrial fusion provides an 'initial metabolic complementation' controlled by mtDNA.
abstract: 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 (ΔΨm) 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'.
authors.affiliation: Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Long
authors.forename: Jinglei
authors.initials: J
authors.lastname: Liu
authors.forename: Haite
authors.initials: H
authors.lastname: Tang
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Feixiang
authors.initials: F
authors.lastname: Bao
authors.forename: Dajiang
authors.initials: D
authors.lastname: Qin
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.forename: Xingguo
authors.initials: X
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002459:Cell Fusion / Q000379:methods; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D006822:Hybrid Cells / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human