Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy

Abstract

Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5′ AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis

“…In addition, different heterotrimeric complexes of AMPK may show specificity for different targets suggesting that this spatial activation is the key for managing energy stress. Consistent with this, Drake et al [241] demonstrated the presence of specific isoforms of mitoAMPK in different tissues in mice and humans. In particular, the isoforms of AMPK α1, α2, β2, and γ1 are physically associated with the OMM, and this mitochondrial localization is conserved in human skeletal muscle and heart.…”

“…Another important question is how AMPK regulates mitophagy in skeletal muscle. In this regard, new PINK1–Parkin-independent mechanisms and the activation of specific, subcellular AMPK pools were reported [ 239 , 240 , 241 ].…”

“…Therefore, in the cytoplasm ULK1 phosphorylates Parkin at Ser108 within 2 min of depolarization treatment. Later, AMPK phosphorylates MFF to induce mitochondrial fission and PINK1 phosphorylates Parkin at Ser65; ( B ) In skeletal muscle, mitoAMPK regulates the spatial specificity of mitophagy in a context of mitochondrial remodeling (by Drake et al) [ 241 ]. Following energetic stress, mitoAMPK is activated in vivo and promotes ULK1-mediated formation of autophagosome which fuse with lysosomes to allow the complete mitochondrial degradation; ( C ) In C2C12 myotubes, AMPK coordinates mitophagy through mitochondrial fission via MFF and TBK1-mediated autophagosomal engulfment via ULK1 activation (by Seabright et al) [ 239 ].…”

Molecular Mechanisms of Exercise and Healthspan

“…Acute exercise causes energetic stress and signaling events that are sensed by AMPK and activates AMPK, leading to a series of phosphorylation cascades to regulate downstream signaling. Recent evidence also suggested that subcellular localization of AMPK may also be of importance, e.g., exercise may specifically activate mitochondria-associated AMPK [ 84 ]. Future studies on subcellular AMPK pools will improve the understanding in how AMPK regulates exercise benefits.…”

Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger

“…A study using AMPKα2 KO mice suggested that AMPKα2 phosphorylates PINK1 at Ser495 to enhance mitophagy and prevent the progression of heart failure induced by pressure overload [ 209 ]. Interestingly, mitochondria-localized AMPK has recently been discovered, and it is suggested that a mitochondrial pool of AMPK responds to local energetics stresses, including cardiac ischemia, to induce mitophagy [ 210 ].…”