Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice
| Autor: | Olle Söder, Luise Landreh, Jan Nedergaard, Nina Atanassova, Natasa Petrovic, Mi Hou, Daniel Edgar, Irina G. Shabalina, Kjell Hultenby, Natalia Gibanova, Konstantin Svechnikov |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Mitochondrial DNA Aging Mitochondrial Diseases Mitochondrial disease Mitochondrion Biology Testicle Biochemistry DNA Mitochondrial Mice Internal medicine Cytochrome b5 Genetics medicine Animals Testosterone Molecular Biology Membrane Potential Mitochondrial Leydig cell Cytochrome c Cytochromes c Leydig Cells medicine.disease Spermatozoa Mitochondria Mice Inbred C57BL Endocrinology medicine.anatomical_structure Cytochromes b5 biology.protein Reactive Oxygen Species Biotechnology |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 29(8) |
| ISSN: | 1530-6860 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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