Photobiomodulation mediates endoplasmic reticulum-mitochondria contact and ameliorates lipotoxicity in MASLD via Mfn2 upregulation

The disruption of mitochondria associated membranes (MAMs) is involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) by modulating endoplasmic reticulum stress (ERS) and mitochondrial malfunction induced by lipotoxicity. Photobiomodulation (PBM), as a non-invasive physical therapy, has been demonstrated to improve cellular metabolism in various diseases. Here we found that PBM with 650 nm ameliorated lipid accumulation and liver injury in high-fat-diet-fed mice. Moreover, MAMs integrity was restored in liver tissues of MASLD after PBM. Correspondingly, PBM enhanced mitochondria-ER colocalization and improved mitochondrial homeostasis in fatty-acid-treated HepG2 cells. Mechanically, Mfn2 expression was selectively elevated by PBM, accompanied by downregulation of PERK, p-PERK, and CHOP. The beneficial effects of PBM were diminished by Mfn2 knockdown, while PERK activity regulated oxidative stress without altering MAMs formation. Thus, PBM relieves lipotoxicity in MASLD by enhancing MAMs integrity via the Mfn2/PERK/CHOP pathway. Our findings may provide evidence for noninvasive physical light therapeutics for lifestyle-related metabolic diseases.

MAMs; MASLD; Mfn2; Mitochondria; PERK; Photobiomodulation.