Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy

by Selleckchem | Jun 03 2023

Background: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear.

Methods: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy.

Results: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well.

Conclusion: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

Comments：

The study found that expression of Jmjd4, a member of the JMJD family proteins, is significantly decreased in the hearts of patients with dilated cardiomyopathy (DCM), a condition characterized by weakened and enlarged heart muscle. The researchers then induced cardiomyocyte-specific deletion of Jmjd4 in mice, which resulted in spontaneous DCM with severely impaired mitochondrial respiration.

The study further found that Pkm2, a less active form of pyruvate kinase, was drastically accumulated in hearts with Jmjd4 deleted. Normally absent in healthy adult cardiomyocytes, Pkm2 is elevated in cardiomyopathy. The researchers found that Jmjd4 interacts with Hsp70 to mediate the degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4.

The researchers also found that TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency and heart failure induced by pressure overload. This suggests that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM and other cardiac diseases with metabolic dysfunction.

Overall, the study identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes and sheds light on the molecular mechanisms underlying the pathogenesis of DCM.