bims-hafaim 2023-10-08 papers

Issue of 2023–10–08
four papers selected by
Kyle McCommis, Saint Louis University

JACC Basic Transl Sci. 2023 Sep;8(9): 1138-1140

Ketone Bodies Preserve Mitochondria Through Epigenetics.

Risa Mukai, Junichi Sadoshima.

Keywords: PGC-1α; epigenetics; heart failure; histone methylation; ketone bodies

DOI: https://doi.org/10.1016/j.jacbts.2023.05.013

Basic Res Cardiol. 2023 Oct 05. 118(1): 42

Mitophagy for cardioprotection.

Allen Sam Titus, Eun-Ah Sung, Daniela Zablocki, Junichi Sadoshima.

Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.

Keywords: Alternative mitophagy; Drp1; Mitochondrial quality control; Mitophagy

DOI: https://doi.org/10.1007/s00395-023-01009-x

JACC Basic Transl Sci. 2023 Sep;8(9): 1123-1137

Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.

Jessica Gambardella, Stanislovas S Jankauskas, Urna Kansakar, Fahimeh Varzideh, Roberta Avvisato, Nella Prevete, Simone Sidoli, Pasquale Mone, Xujun Wang, Angela Lombardi, Gaetano Santulli.

Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.

Keywords: BHB; heart failure; histone methylation; ischemia; mitochondria; myocardial infarction; β-hydroxybutyrate

DOI: https://doi.org/10.1016/j.jacbts.2023.03.014

Life Sci Alliance. 2023 Dec;pii: e202302116. [Epub ahead of print]6(12):

Improving lysosomal ferroptosis with NMN administration protects against heart failure.

Mikako Yagi, Yura Do, Haruka Hirai, Kenji Miki, Takahiro Toshima, Yukina Fukahori, Daiki Setoyama, Chiaki Abe, Yo-Ichi Nabeshima, Dongchon Kang, Takeshi Uchiumi.

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD+) levels, leading to impaired lysosomal acidification and autophagy. In this study, we investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.

DOI: https://doi.org/10.26508/lsa.202302116