title: Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice.
abstract: Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in tissues during aging in animals and humans and are the basis for mitochondrial diseases. Testosterone synthesis occurs in the mitochondria of Leydig cells. Mitochondrial dysfunction (as induced here experimentally in mtDNA mutator mice that carry a proofreading-deficient form of mtDNA polymerase γ, leading to mitochondrial dysfunction in all cells types so far studied) would therefore be expected to lead to low testosterone levels. Although mtDNA mutator mice showed a dramatic reduction in testicle weight (only 15% remaining) and similar decreases in number of spermatozoa, testosterone levels in mtDNA mutator mice were unexpectedly fully unchanged. Leydig cell did not escape mitochondrial damage (only 20% of complex I and complex IV remaining) and did show high levels of reactive oxygen species (ROS) production (>5-fold increased), and permeabilized cells demonstrated absence of normal mitochondrial function. Nevertheless, within intact cells, mitochondrial membrane potential remained high, and testosterone production was maintained. This implies development of a compensatory mechanism. A rescuing mechanism involving electrons from the pentose phosphate pathway transferred via a 3-fold up-regulated cytochrome b5 to cytochrome c, allowing for mitochondrial energization, is suggested. Thus, the Leydig cells escape mitochondrial dysfunction via a unique rescue pathway. Such a pathway, bypassing respiratory chain dysfunction, may be of relevance with regard to mitochondrial disease therapy and to managing ageing in general.
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Shabalina
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Luise
authors.initials: L
authors.lastname: Landreh
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Edgar
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Mi
authors.initials: M
authors.lastname: Hou
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gibanova
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Nina
authors.initials: N
authors.lastname: Atanassova
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Natasa
authors.initials: N
authors.lastname: Petrovic
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Olle
authors.initials: O
authors.lastname: Söder
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria jan.nedergaard@su.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.affiliation: *Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren's Children Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; and Institute of Experimental Morphology, Pathology and Anthropology with Museum, Sofia, Bulgaria.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Svechnikov
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015786:Cytochromes b5 / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D007985:Leydig Cells / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism; D013739:Testosterone / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013739:Testosterone; D045304:Cytochromes c; D015786:Cytochromes b5
keywords: cytochrome b5; reactive oxygen species; respiratory chain deficiency; testosterone synthesis