ISSN: 1449-1907International Journal of Medical Sciences
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Int J Med Sci 2024; 21(6):983-993. doi:10.7150/ijms.94577 This issue Cite
Research Paper
Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis
1. Luoyang Branch of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Luoyang Hospital of TCM, Luoyang 471000, China.
2. Daqing Oilfield General Hospital, Daqing 163000, China.
3. Brandeis University, Waltham, MA 02453, USA.
4. Heilongjiang University of Chinese Medicine, Harbin 150040, China.
5. First Afliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China.
6. Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
Abstract
Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.
Keywords: PKM2, PHB2, septic cardiomyopathy, mitochondrial biogenesis
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