Mitochondrial Dysfunction in Obesity and Reproduction

Abstract

Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Because of the central role of mitochondria in energy production, heme biosynthesis, calcium buffering, steroidogenesis, and apoptosis signaling within cells, understanding the molecular mechanisms behind mitochondrial dysregulation and its potential implications in disease is critical. This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders, focusing on metabolic alterations and reproductive abnormalities. Evidence is presented from studies in different human populations, and rodents with genetic manipulations of pathways known to affect mitochondrial function.

Keywords: insulin resistance; lipid accumulation; mitochondrial dynamics; mitochondrial function; mitophagy; ovarian dysfunction; oxidative stress.

Figure 1.

Mitochondrial dysfunction can involve mutation of mitochondrial DNA, reduction in mitochondrial content and/or biogenesis, impaired dynamics (fission/fusion), impaired mitophagy, failure in bioenergetics, reduced enzyme activity, augmented oxidative stress, or an imbalance in calcium homeostasis that cumulatively lead to decreased glucose and lipid oxidation. This disruption in lipid oxidation leads to lipid accumulation, which is manifested as an increase in active lipid intermediates, such as diacylglycerols (DAG) and ceramide (CER) that can inhibit insulin action. The decrease in substrate oxidation and reduced oxidative phosphorylation leads to diminished electron flow through the electron transport chain (ETC), which subsequently causes electron leakage and superoxide generation, followed by oxidative stress and mitochondria damage. Mitophagy maintains mitochondrial homeostasis by removing damaged mitochondria. Impaired mitophagy exacerbates the problem by failing to remove damaged mitochondria leading to further increases in oxidative stress and mitochondrial damage.

Figure 2.

A schematic of the mature follicle in the ovary depicting disrupted mitochondrial homeostasis due to increased mitochondrial content in the mature preovulatory oocytes and granulosa cells, which increases the probability of mitochondrial DNA (mtDNA) mutations, activation of unfolded protein response, and increased production of reactive oxygen species (ROS) that ultimately attenuate oocyte quality and reproduction.