Hundreds of mitochondria in every cell work to produce adenosine triphosphate (ATP), a chemical energy store molecule needed to power cell activities. Mitochondria evolved from symbiotic bacteria, and are now fully integrated as components of the cell, with much of their original DNA moved into the cell nucleus. Mitochondria become dysfunctional with age, reducing their production of ATP, increasing oxidative byproducts, and causing maladaptive inflammatory reactions. This is an important contribution to the disruption of cell and tissue function that takes place in aged tissues.
Unfortunately, mitochondrial dysfunction, while well established and readily measured, is also enormously complex and incompletely understood. Many different contributing mechanisms are plausible, but it is a challenge to determine which of them are more or less important than the others. So far, attempts to improve mitochondrial function in older individuals via pharmacology and supplements have struggled to improve on the effects of exercise, suggesting that the mechanisms targeted are not those with the largest effects on function, or at least are not in and of themselves sufficient to improve function.
In today's open access paper, researchers outline one of the many contributing issues to mitochondrial dysfunction. Their focus is on muscle tissue, but much of the underlying problem generalizes to other tissues. The structure of the inner mitochondrial membrane relies upon the presence of cardiolipin, but cardiolipin production declines with age. This triggers changes in mitochondrial function that muscle tissue reacts to with remodeling of the distribution of fiber type in additional to any other issues that arise. Experiments in a mouse lineage engineered to lack cardiolipin suggests that replacing lost cardiolipin can help to restore function, but one would want to see that same study repeated in aged mice before taking it at face value.
Skeletal muscle is composed of fiber types that span a continuum of contractile and metabolic properties, enabling the tissue to meet diverse functional demands. Along this spectrum, slow-twitch (type I) fibers show high mitochondrial oxidative capacity, whereas fast-twitch fibers comprise both oxidative (type IIa) and glycolytic (type IIx and IIb) subtypes that rely differently on oxidative versus glycolytic metabolism for force generation. Diminished mitochondrial function disrupts systemic energy homeostasis and is a hallmark of myopathies and aging. Yet, seemingly paradoxically, myopathies and aging also lead to selective atrophy of glycolytic fibers and a shift toward oxidative metabolism. The timing and mechanisms driving this fiber-type-specific shift remain unclear. Whether diminished mitochondrial function has a causal role in eliciting adaptive measures or is merely a marker of age- and disease-related decline is unknown.
Mitochondrial function is heavily shaped by the inner mitochondrial membrane (IMM), which coordinates cellular and organismal homeostasis by modulating macronutrient exchange, bioenergetic capacity, fusion and fission, and interactions with other organelles. The IMM's distinct curvature is conferred by a unique lipid composition, most notably the phospholipid cardiolipin (CL). Here we show that synthesis of cardiolipin causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle.
By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell-autonomously orchestrate fiber-type adaptations in aging and myopathies.
View the full article at FightAging
