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Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent
Jiaxi Ren1, Bin Ren2, Tong Fu3
1Luoyang Branch of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Luoyang Hospital of TCM, Luoyang 471000, 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.
Insights
Pyruvate kinase M2 (PKM2) protects against septic cardiomyopathy. PKM2 deficiency worsens heart dysfunction and inflammation by impairing mitochondrial biogenesis, but restoring prohibitin 2 (PHB2) offers protection.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Inflammation Research
Background:
- Septic cardiomyopathy is a severe complication of sepsis.
- Pyruvate kinase M2 (PKM2) has shown protective effects in previous studies.
- The precise role of PKM2 in sepsis-induced heart dysfunction requires further elucidation.
Purpose of the Study:
- To investigate the role of cardiomyocyte-specific PKM2 in attenuating lipopolysaccharide (LPS)-induced myocardial dysfunction.
- To explore the impact of PKM2 on mitochondrial biogenesis and prohibitin 2 (PHB2) in septic cardiomyopathy.
- To determine if restoring PHB2 levels can mitigate PKM2 deficiency-induced cardiac damage.
Main Methods:
- Utilized cardiomyocyte-specific PKM2 knockout mice.
- Induced myocardial dysfunction using LPS administration.
- Assessed cardiac contractile function, relaxation, and inflammation.
- Analyzed mitochondrial function, including ATP production, respiratory complex activities, and reactive oxygen species (ROS) generation.
- Investigated mitochondrial biogenesis pathways.
- Employed PHB2 adenovirus to restore PHB2 levels in PKM2-deficient hearts.
Main Results:
- PKM2 deletion exacerbated LPS-induced myocardial dysfunction and inflammation.
- LPS impaired mitochondrial function, with worsened effects in PKM2-deficient hearts.
- PKM2 deficiency aggravated LPS-induced disruption of mitochondrial biogenesis.
- Overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and improved mitochondrial function.
- PHB2 overexpression mitigated the detrimental effects of PKM2 deletion.
Conclusions:
- PKM2 plays a critical role in protecting against septic cardiomyopathy.
- PKM2 deficiency impairs mitochondrial biogenesis, leading to mitochondrial damage, inflammation, and cardiac dysfunction.
- Restoring PHB2 levels can counteract the adverse effects of PKM2 deficiency in septic cardiomyopathy.
- These findings provide novel insights into the molecular mechanisms of septic cardiomyopathy and suggest PHB2 as a potential therapeutic target.
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