Increased Total mtDNA Copy Number Cures Male Infertility Despite Unaltered mtDNA Mutation Load

Mutations of mtDNA cause mitochondrial diseases and are implicated in age-associated diseases and aging. Pathogenic mtDNA mutations are often present in a fraction of all mtDNA copies, and it has been widely debated whether the proportion of mutant genomes or the absolute number of wild-type molecules determines if oxidative phosphorylation (OXPHOS) will be impaired. Here, we have studied the male infertility phenotype of mtDNA mutator mice and demonstrate that decreasing mtDNA copy number worsens mitochondrial aberrations of spermatocytes and spermatids in testes, whereas an increase in mtDNA copy number rescues the fertility phenotype and normalizes testes morphology as well as spermatocyte proteome changes. The restoration of testes function occurs in spite of unaltered total mtDNA mutation load. We thus demonstrate that increased copy number of mtDNA can efficiently ameliorate a severe disease phenotype caused by mtDNA mutations, which has important implications for developing future strategies for treatment of mitochondrial dysfunction.

Cell metabolism. 2017 Aug 01 [Epub]

Min Jiang, Timo Eino Sakari Kauppila, Elisa Motori, Xinping Li, Ilian Atanassov, Kat Folz-Donahue, Nina Anna Bonekamp, Sara Albarran-Gutierrez, James Bruce Stewart, Nils-Göran Larsson

Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany., Proteomics Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany., FACS and Imaging Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany., Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: .

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