ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue

Abstract

Mitochondria play a central role in the function of brown adipocytes (BAs). Although mitochondrial biogenesis, which is indispensable for thermogenesis, is regulated by coordination between nuclear DNA transcription and mitochondrial DNA transcription, the molecular mechanisms of mitochondrial development during BA differentiation are largely unknown. Here, we show the importance of the ER-resident sensor PKR-like ER kinase (PERK) in the mitochondrial thermogenesis of brown adipose tissue. During BA differentiation, PERK is physiologically phosphorylated independently of the ER stress. This PERK phosphorylation induces transcriptional activation by GA-binding protein transcription factor α subunit (GABPα), which is required for mitochondrial inner membrane protein biogenesis, and this novel role of PERK is involved in maintaining the body temperatures of mice during cold exposure. Our findings demonstrate that mitochondrial development regulated by the PERK–GABPα axis is indispensable for thermogenesis in brown adipose tissue.

ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk—Signaling Beyond (ER) Stress Response

“…This PERK phosphorylation induces transcriptional activation by GA-binding protein transcription factor α subunit (GABPα), which is required for mitochondrial inner membrane protein biogenesis. This study also demonstrated that p-PERK controls mitochondrial and thermogenic gene expression via transcriptional activation by GABPα and UCP1-mediated thermogenesis in vitro and in vivo [164].…”

A PERKy way to make mitochondrial cristae

“…In a series of related recent papers, notably the most recent report by Latorre-Muro et al [2], as well as in a paper by Kato et al [3], this plasticity of BAT has been used as a means to delineate the molecules that direct cristae formation, not only in brown adipocytes but probably in all cells in the body (see also Balsa et al [4]). Because many mitochondrial proteins are synthesized in the endoplasmic reticulum (ER), it is perhaps not so surprising that a kinase in the ER that is located at mitochondria-associated ER membranes (MAMs) directs the process.…”

“…They also found that PERK stimulated cristae formation, but this took place via another pathway. PERK was then seen to be physiologically phosphorylated independently of the ER stress pathway, and was found to be of importance for cristae formation also in brown adipocytes, although the mechanism remained undefined [3]. Latorre-Muro and colleagues [2] have now identified the alternative pathway by which PERK accomplishes this activation of cristae formation.…”

“…O-GlcNAcetylation activates TOMM70, and more MIC19 is transported into the intermembrane space, leading to more MICOS complex activity, and thus to mitochondrial cristae formation. Kato et al [3] additionally identified a further downstream PERK pathway that induces transcriptional activation of GABPα (also known as NRF2), leading to increased synthesis of respiratory chain…”

“…It seems, however, that the pathways induced by tunicamycin and those induced by norepinephrine are not the same. Further, the phosphorylation sites on PERK are different [3]. A remaining question thus concerns the intracellular pathway leading from norepinephrine stimulation of the brown adipocyte to PERK activation, a pathway that would then occur in parallel with that leading to lipolysis, UCP1 activation, and heat production.…”