Fight Aging!

Mitophagy is a quality control process that removes damaged and worn mitochondria, sending them to a lysosome for disassembly. Mitochondria are essential to cell function, a herd of hundreds of these bacteria-like organelles present in every cell. Active mitophagy ensures that this population of mitochondria remains usefully functional, providing the cell with a sufficient supply of the energy store molecule adenosine triphosphate (ATP). When mitophagy falters, as occurs throughout the body with age, for reasons that remain incompletely understood, the outcome is that mitochondrial function, cell function, and tissue function are all negatively affected. A better understanding of the triggers of the mitophagy process could lead to the development of compensatory therapies that at least partially restore lost mitochondrial function, and thus improve health and turn back aging in the old.

Mitochondria form a complex, interconnected reticulum that is maintained through orchestrated remodeling processes, such as biogenesis, dynamic fission and fusion, and targeted degradation of damaged/dysfunctional mitochondria, called mitophagy. These remodeling processes are collectively known as mitochondrial quality control and are initiated by various cues to maintain energetic homeostasis, which is particularly important for tissues with high-energy demands (e.g., skeletal muscle and heart). While the reticulum appears to respond to energetic demand uniformly, mitochondrial quality control acts with remarkable subcellular precision. For example, in both skeletal muscle and heart, impaired or damaged regions of mitochondria are separated from the functional reticulum in response to certain cellular signals, setting the stage for their degradation by mitophagy. However, what governs the spatial specificity of this process is poorly understood.

The cellular energy sensor AMPK senses cellular energy status by monitoring AMP and/or ADP levels. AMP and/or ADP bind to the γ subunit of AMPK, resulting in a conformational change. Muscle-specific knockout of both α subunit isoforms impairs exercises capacity and mitochondrial oxidative capacity, clearly linking energy sensing of AMPK to mitochondrial function as well as tissue function. Indeed, AMPK activation promotes mitochondrial fission in vitro through its direct substrate mitochondrial fission factor (Mff). We and others have previously demonstrated that induction of mitophagy in response to energetic stress (e.g., exercise, fasting, etc.) is controlled by AMPK-dependent mechanisms.

To reconcile the subcellular specificity of mitochondrial quality control with the fact that exercise and other energetic stresses increase ADP and AMP, the known activators of AMPK, we hypothesized that a proportion and/or subtype of AMPK is localized at mitochondria. This pool of AMPK may serve as a gauge of energetic cues, particularly when and where ATP production through oxidative phosphorylation becomes limited. Herein, we uncovered that a particular combination of subunits of AMPK are localized to mitochondria in a variety of tissues, including skeletal muscle and heart in both mice and humans, which we term mitoAMPK.

We show that mitoAMPK is localized to the outer mitochondrial membrane and is activated in response to various stimuli of mitochondrial energetic stress. mitoAMPK activity and activation are spatially variable across the mitochondrial reticulum. Finally, we present evidence that suggests activation of mitoAMPK in skeletal muscle is required for mitophagy in vivo. Discovery of a pool of AMPK on mitochondria and its importance for mitochondrial quality control highlights the complexity of energetic monitoring in vivo and could facilitate development of strategies of targeting mitochondrial energetics to treat diseases related to impaired mitochondrial function.

Link: https://doi.org/10.1073/pnas.2025932118