The role of mitochondria in health and disease

Abstract

Mitochondria play a key role in energy metabolism in many tissues, including skeletal muscle and liver. Inherent disorders of mitochondria such as DNA deletions cause major disruption of metabolism and can result in severe impairment or death. However, the occurrence of such disorders is extremely rare and cannot account for the majority of metabolic disease. Recently, mitochondrial dysfunction of a more subtle nature in skeletal muscle has been implicated in the pathology of chronic metabolic disease characterized by insulin resistance such as obesity, type 2 diabetes mellitus, and aging. This hypothesis has been substantiated by work from Shulman and colleagues, showing that reduced mitochondrial oxidative capacity underlies the accumulation of intramuscular fat causing insulin resistance with aging. However, recent work by Nair and coworkers has demonstrated that mitochondrial activity may actually be higher in persons exposed to high-calorie diet leading to obesity, suggesting that the accumulation of intramuscular fat and associated fatty acid metabolites may be directly responsible for the development of insulin resistance, independent of mitochondrial function. These inconsistent findings have promoted ongoing investigation into mitochondrial function to determine whether impaired function is a cause or consequence of metabolic disorders.

Figure 1

Electron transport chain (ETC) of mitochondria. Energy obtained through the transfer of electrons (white arrows) down the ETC is used to pump protons (blue arrows) from the matrix into the intermembrane space, creating an electrochemical proton gradient across the mitochondrial inner membrane. This gradient allows ATP synthase to use the flow of H⁺ through the enzyme back into the matrix to generate ATP from ADP and inorganic phosphate. Complex I (NADH coenzyme Q reductase) accepts electrons from the electron carrier nicotinamide adenine dinucleotide (NADH), and passes them to coenzyme Q (ubiquinone), which also receives electrons from complex II (succinate dehydrogenase). Ubiquinone passes electrons to complex III (cytochrome bc₁), which passes them to cytochrome c (cyt c). Cyt c passes electrons to Complex IV (cytochrome c oxidase), which uses the electrons and hydrogen ions to reduce molecular oxygen to water. Sites of superoxide radical production occur primarily at Complexes I and III, particularly under conditions such as high proton gradient. Source: Obesity Online Slide Library, www.obesityonline.org.

Figure 2

Rare mitochondrial diseases owing to DNA deletions and mutations usually results in severe functional impairment leading to myopathy, severe weakness and often death. The role of mitochondrial function/dysfunction in more common conditions such as aging, obesity, insulin resistance, and type 2 diabetes is speculative and controversial, and may be mediated through environmental factors such as poor diet and inactivity, and/or through common DNA mutations or decreased cellular energy requirement.