The peroxisomal enzyme, FAR1, is induced during ER stress in an ATF6-dependent manner in cardiac myocytes

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 320; no. 5; p. H1813
• Main Authors: Marsh, Kayleigh G, Arrieta, Adrian, Thuerauf, Donna J, Blackwood, Erik A, MacDonnell, Lauren, Glembotski, Christopher C
• Format: Journal Article
• Language: English
• Published: United States 01-05-2021
• Subjects: Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; Aldehyde Oxidoreductases - biosynthesis; Aldehyde Oxidoreductases - genetics; Animals; Animals, Newborn; Cell Hypoxia; Cell Survival; Cells, Cultured; Endoplasmic Reticulum Stress - drug effects; Enzyme Induction; Hydrogen Peroxide - toxicity; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Oxidative Stress; Peroxisomes - drug effects; Peroxisomes - enzymology; Peroxisomes - metabolism; Rats; Tunicamycin - toxicity; peroxisome; FAR1; ischemia-reperfusion; ATF6; cardiomyocyte
• ISSN: 1522-1539
• DOI: 10.1152/ajpheart.00999.2020

Although peroxisomes have been extensively studied in other cell types, their presence and function have gone virtually unexamined in cardiac myocytes. Here, in neonatal rat ventricular myocytes (NRVM) we showed that several known peroxisomal proteins co-localize to punctate structures with a morphology typical of peroxisomes. Surprisingly, we found that the peroxisomal protein, fatty acyl-CoA reductase 1 (FAR1), was upregulated by pharmacological and pathophysiological ER stress induced by tunicamycin (TM) and simulated ischemia-reperfusion (sI/R), respectively. Moreover, FAR1 induction in NRVM was mediated by the ER stress sensor, activating transcription factor 6 (ATF6). Functionally, FAR1 knockdown reduced myocyte death during oxidative stress induced by either sI/R or hydrogen peroxide (H
O
). Thus, Far1 is an ER stress-inducible gene, which encodes a protein that localizes to peroxisomes of cardiac myocytes, where it reduces myocyte viability during oxidative stress. Since FAR1 is critical for plasmalogen synthesis, these results imply that plasmalogens may exert maladaptive effects on the viability of myocytes exposed to oxidative stress.
The peroxisomal enzyme, FAR1, was shown to be an ER stress- and ATF6-inducible protein that localizes to peroxisomes in cardiac myocytes. FAR1 decreases myocyte viability during oxidative stress.