Impaired Mitochondria Promote Aging-Associated Sebaceous Gland Dysfunction and Pathology

Abstract

Mitochondrial dysfunction is one of the hallmarks of aging. Changes in sebaceous gland (SG) function and sebum production have been reported during aging. Herein, we report the direct effects of mitochondrial dysfunction on SG morphology and function. We utilized a mitochondrial DNA (mtDNA) depleter mouse as a model for introducing mitochondrial dysfunction in the whole animal. We characterized the effects on skin SGs and modified SGs of the eyelid, lip, clitoral, and preputial glands. The mtDNA depleter mice show gross morphologic and histopathologic changes in SGs associated with increased infiltration by mast cells, neutrophils, and polarized macrophages. Consistently, there was increased expression of proinflammatory cytokines. The inflammatory changes were associated with abnormal sebocyte accumulation of lipid, defective sebum delivery at the skin surface, and the up-regulation of key lipogenesis-regulating genes and androgen receptor. The mtDNA depleter mice expressed aging-associated senescent marker. We also observed increased sebocyte proliferation and aberrant expression of stem cell markers. These studies provide, for the first time, a causal link between mitochondrial dysfunction and abnormal sebocyte function within sebaceous and modified SGs throughout the whole body of the animal. Our studies suggest that mtDNA depleter mouse may serve as a novel tool to develop targeted therapeutics to address SG disorders in aging humans.