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

Abstract

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.

Response by Tang et al to Letter Regarding Article, “Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy”

“…1 Jmjd4, however, belongs to those smaller Jmjd proteins well below 100 kDa, which have few known domains besides the Jmjc domain and normally lack histone demethylase activity. 1 In fact, Pkm2, identified in our work, 2 is among a handful Jmjd4 substrates characterized so far, the list of which may certainly grow with future studies.…”

“…2 It is not uncommon that phenotypes of loss-of-function are not the opposite of gain-of-function, or enzymatic activation, in a biological system, because deviation toward either direction from the optimal quantity, or activity, of a tightly regulated key protein may deteriorate cellular and tissue homeostasis. In addition, although we did not genetically manipulate Pkm2 in our study, 2 the mutual compensation between Pkm1 and Pkm2 , which differ by only 1 alternatively spliced exon, is a well-documented phenomenon. An earlier study 4 evidently showed that when the Pkm1 - or Pkm2 -specific exon is deleted in cardiomyocyte, the expression of the other elevates to compensate.…”

“…It is intriguing that Ni et al showed that cardiomyocyte-specific knockout and overexpression of Pkm2 exacerbated and ameliorated transverse aortic constriction-induced cardiac hypertrophy, respectively, 3 whereas we observed Pkm2 accumulation upon pressure overload, and promoting its enzymatic activity is protective against heart failure. 2 It is not uncommon that phenotypes of loss-of-function are not the opposite of gain-of-function, or enzymatic activation, in a biological system, because deviation toward either direction from the optimal quantity, or activity, of a tightly regulated key protein may deteriorate cellular and tissue homeostasis. In addition, although we did not genetically manipulate Pkm2 in our study, 2 the mutual compensation between Pkm1 and Pkm2 , which differ by only 1 alternatively spliced exon, is a well-documented phenomenon.…”

Letter by Li et al Regarding Article, “Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy”

“…We read with interest the article by Tang et al 1 reporting that pressure overload reduces myocardial Jmjd4 expression and leads to the accumulation of inactive Pkm2 dimer, which results in progressive dilated cardiomyopathy and heart failure. Jmjd4 hydroxylates Pkm2 to promote its degradation through chaperone-mediated autophagy.…”

Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis

“…Pyruvate kinase M2 (PKM2) is a specific isoform of the pyruvate kinase enzyme, crucial for cellular metabolism, particularly in glycolysis. Its involvement spans various physiological and pathological processes, including cell proliferation, metabolic regulation, and tumorigenesis [8][9][10]. The pivotal role of PKM2 in regulating cellular energy metabolism and growth is of profound interest in disease research and therapy.…”