Mitochondrial DNA Depletion Linked to Depletion Syndromes

Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases and other human pathologies such as cardiovascular disease, diabetes, age-associated neurological disorders and cancer.

To study the involvement of mitochondrial DNA in these processes, investigators at the University of Alabama (Birmingham, USA) created a mouse model with a dominant-negative mutation in the polymerase domain of the POLG1 (DNA polymerase gamma 1, accessory subunit) gene, which induced depletion of mtDNA in various tissues. The mutation in this mouse model was induced by addition of the antibiotic doxycycline to the food or drinking water, which caused depletion of mitochondrial DNA, as the enzyme to replicate mtDNA was inactivated.

The investigators reported in the July 20, 2018, online edition of the journal Cell Death and Disease that these "mtDNA-depleter" mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. They demonstrated that ubiquitous depletion of mtDNA in mice led to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses.

Removal of doxycycline from the diet turned off mutant POLG1 transgene expression, which restored mitochondrial function, as well as normalizing the skin and hair, to wild-type levels.

“To our knowledge, this observation is unprecedented,” said senior author Dr. Keshav Singh, professor of genetics at the University of Alabama. “This mouse model should provide an unprecedented opportunity for the development of preventive and therapeutic drug development strategies to augment the mitochondrial functions for the treatment of aging-associated skin and hair pathology and other human diseases in which mitochondrial dysfunction plays a significant role.”

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