University of Virginia (UVA) School of Medicine scientists report a major advance in understanding the way our bodies ensure the proper functioning of mitochondria. The findings could open the door to better treatments for many common diseases, including Alzheimer’s and diabetes, according to Zhen Yan, PhD, and colleagues, who describe (“Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy“) in PNAS how cells sense problems and perform quality control on mitochondria.

“Mitochondria are the center of universe to me since literally all cells in our body rely on mitochondria for energy production and must have a bulletproof system to ensure the powerhouses are functioning properly,” said Yan, the director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center. “Chronic diseases, also known as noncommunicable diseases, such as diabetes, heart failure and Alzheimer’s disease that catastrophically impact so many individuals, families and the whole society are caused by problems of the mitochondria in the cells.”

Yan and his team discovered special sensors on the outer membrane surrounding the mitochondria in various tissues in both mice and humans. These sensors detect “energetic stress,” such as that caused by exercise or fasting, and signal for damaged mitochondria to be degraded and removed. This essential cleanup process (mitophagy) and its existence was first suggested more than 100 years ago. But how it works has never been fully understood. Yan’s new research offers long-sought answers.

“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,” write Yan and his team of investigators.

“…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.”

The researchers found that the mitochondrial sensors (mitoAMPK) exist in slightly different forms in different tissues. For example, one type seemed particularly active in skeletal muscle. In a new scientific paper outlining their findings, the researchers describe the variety of sensors as “unexpectedly complex.” They go on to outline how these sensors provide a vital damage-control system that safeguards our cellular energy supply.

One finding of the study that Yan finds extremely exciting: Treating mice with  metformin, the most effective, first-line anti-diabetes drug, activates mitoAMPK in skeletal muscles without activating AMPK in the other parts of the cells. The finding illustrates the importance of activating mitoAMPK and mitochondrial quality control in treatment of a common chronic disease that is known to be caused by accumulation of dysfunctional mitochondria in our body. It also explains why regular exercise is so powerful in preventing and treating such diseases.

The new insights gained into mitochondrial quality control could boost efforts to develop new treatments for non-communicable diseases that have reached pandemic proportions and are estimated to cause 71% of all deaths.

Yan, who is part of UVA’s Division of Cardiovascular Medicine, says it will be important for doctors to better understand how specific diseases interfere with mitochondrial function. And his new findings set the stage for that.

“We have developed genetic models for pinpointing the key steps of mitoAMPK activation and are on our way to discover the magic molecules that are controlled by mitoAMPK,” notes Yan. “The findings taught us a lot about the beauty of the sensor system in our body. Society should definitely take advantage of these findings to promote regular exercise for health and disease prevention and develop effective exercise-mimetic drugs.”

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