Browsing by Author "Zhang, Mei"

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    Endurance Exercise Training Mitigates Diastolic Dysfunction in Diabetic Mice Independent of Phosphorylation of Ulk1 at S555
    Guan, Yuntian; Zhang, Mei; Lacy, Christie; Shah, Soham; Epstein, Frederick H.; Yan, Zhen (MDPI, 2024-01-03)
    Millions of diabetic patients suffer from cardiovascular complications. One of the earliest signs of diabetic complications in the heart is diastolic dysfunction. Regular exercise is a highly effective preventive/therapeutic intervention against diastolic dysfunction in diabetes, but the underlying mechanism(s) remain poorly understood. Studies have shown that the accumulation of damaged or dysfunctional mitochondria in the myocardium is at the center of this pathology. Here, we employed a mouse model of diabetes to test the hypothesis that endurance exercise training mitigates diastolic dysfunction by promoting cardiac mitophagy (the clearance of mitochondria via autophagy) via S555 phosphorylation of Ulk1. High-fat diet (HFD) feeding and streptozotocin (STZ) injection in mice led to reduced endurance capacity, impaired diastolic function, increased myocardial oxidative stress, and compromised mitochondrial structure and function, which were all ameliorated by 6 weeks of voluntary wheel running. Using CRISPR/Cas9-mediated gene editing, we generated non-phosphorylatable Ulk1 (S555A) mutant mice and showed the requirement of p-Ulk1at S555 for exercise-induced mitophagy in the myocardium. However, diabetic Ulk1 (S555A) mice retained the benefits of exercise intervention. We conclude that endurance exercise training mitigates diabetes-induced diastolic dysfunction independent of Ulk1 phosphorylation at S555.
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    Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy
    Drake, Joshua C.; Wilson, Rebecca J.; Laker, Rhianna C.; Guan, Yuntian; Spaulding, Hannah R.; Nichenko, Anna S.; Shen, Wenqing; Shang, Huayu; Dorn, Maya; Huang, Kian; Zhang, Mei; Bandara, Aloka B.; Brisendine, Matthew H.; Kashatus, Jennifer A.; Sharma, Poonam R.; Young, Alexander; Gautam, Jitendra; Cao, Ruofan; Wallrabe, Horst; Chang, Paul A.; Wong, Michael; Desjardins, Eric M.; Hawley, Simon A.; Christ, George J.; Kashatus, David F.; Miller, Clint L.; Wolf, Matthew J.; Periasamy, Ammasi; Steinberg, Gregory R.; Hardie, D. Grahame; Yan, Zhen (National Academy of Sciences, 2021-09-14)
    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.