Physical inactivity and overeating leading to obesity and diabetes are both linked to increased risk of age-related chronic diseases. By contrast, caloric restriction and physical activity promote health. However, the cellular mechanisms that link the metabolic state to long-term health outcomes have remained unclear. Damage to mitochondrial DNA (mtDNA), which accumulates with aging in diseased human tissues and with diabetes complications, has been shown in animal models to recapitulate several features of aging. Importantly, mitochondrial morphology, function, and the integrity of mtDNA directly respond to the metabolic state. The oversupply of cells with excess lipids and glucose (i.e., hyperglycemia) fragments mitochondria, increases mitochondrial reactive oxygen species production, and promotes the accumulation of mtDNA damage. In turn, the limited supply of energy substrates promotes fusion and elongation of mitochondria and limits accumulation of mtDNA damage. Here we propose a model in which mitochondrial dynamics (fusion/fission) integrate systemic metabolic information and control the stability of the mitochondrial genome, thus helping to mediate the effects of physical activity, inactivity, and calorie intake on health outcomes.
It is well established both epidemiologically and clinically that physical inactivity and behaviors leading to weight gain are associated with elevated risk of most age-related diseases as well as mortality (1). However, the underlying mechanisms mediating these effects are not fully explained. Conversely, the health promoting and life-extending effects of caloric restriction and physical activity are well described (2,3). Nonetheless, the exact mechanisms underlying the health benefits of these interventions, including the reduced risk of most age-related metabolic diseases and diabetes complications, have not been fully elucidated. Here we present a common mechanism that may account for the combined long-term effects of physical activity/inactivity and diet on health outcomes and aging. Improved understanding of the acute cellular events initiated by fluctuations in the metabolic state may facilitate development of targeted therapies and could be leveraged to nurture behavior change, thereby providing new opportunities to promote metabolic health.
Mitochondria are cellular organelles that transform energetic substrates (e.g., lipids and glucose) and oxygen into energy. These organelles retain several remnant characteristics of their past lives as aerobic bacteria, including a double membrane, circular DNA molecules, and the ability to interact with each other (4). Constant mitochondrion-mitochondrion interactions take place through dynamic processes of membrane fusion and fission. These interactions alter mitochondrial morphology and simultaneously modulate the organelles’ function (5). Importantly, mitochondrial morphology and function undergo significant transitions in response to changes in the cellular metabolic state, which are defined here as the balance between the supply of energetic substrates and cellular energy demand. In turn, mitochondrial fusion and fission control the integrity of mtDNA whereby normal mitochondrial fusion promotes stability of the mitochondrial genome and excessive mitochondrial fission leads to preferential accumulation of mutated mtDNA (6,7).
Increased amounts of mutated mtDNA in postmitotic tissues are a feature of aging and of age-related neurodegenerative diseases (8). Because the mitochondrial genome encodes essential elements of the electron transport chain that fuels ATP synthesis, damage to mtDNA causes severe bioenergetic failure. Evidence from mouse models of mtDNA diseases caused by a mutated proofreading domain in the gene encoding the mitochondrial polymerase γ (PolG) has demonstrated that high levels of mutated mtDNA generate signs consistent with premature aging. This is observed across organ systems and reduces life span in mice by up to 50% (9,10). The clonal expansion of mutated mtDNA copies toward high heteroplasmy levels leads to respiratory chain deficiency and impacts mitochondrial function. This causes cell loss via apoptosis and reduction of whole-body exercise tolerance (8), both features of normal aging. Thus, along with other putative mechanisms such as cellular quality control processes (autophagy/mitophagy) (11,12), telomere dynamics (13), and antioxidant/anti-inflammatory mechanisms (14), chronic metabolic imbalances causing prolonged alterations in mitochondrial morphology could influence both mitochondrial function and the integrity of the mitochondrial genome. In turn, these alterations may modify disease susceptibility and long-term health outcomes.