Journal
FASEB JOURNAL
Volume 34, Issue 7, Pages 9372-9392Publisher
WILEY
DOI: 10.1096/fj.202000173R
Keywords
endothelial cells; mitochondrial dynamics; mitophagy; mitochondrial fusion; mitochondrial fission
Categories
Funding
- National Institutes of Health [1R01 CA220237-01A1, 2CA136494, CA213278, CA157481, 1R01HL120585]
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Mutations in the human cystathionine beta synthase (CBS) gene are known to cause endothelial dysfunction responsible for cardiovascular and neurovascular diseases. CBS is the predominant hydrogen sulfide (H2S)-producing enzyme in endothelial cells (ECs). Recently, H2S was shown to attenuate ROS and improve mitochondrial function. Mitochondria are metabolic organelles that actively transform their ultrastructure to mediate their function. Therefore, we questioned whether perturbation of CBS/H2S activity could drive mitochondrial dysfunction via mitochondrial dynamics in ECs. Here we demonstrate that silencing CBS induces mitochondria fragmentation, attenuates efficient oxidative phosphorylation, and decreases EC function. Mechanistically, CBS silencing significantly elevates ROS production, thereby leading to reduced mitofusin 2 (MFN2) expression, decouple endoplasmic reticulum-mitochondria contacts, increased mitochondria fission, enhanced receptor-mediated mitophagy, and increased EC death. These defects were significantly rescued by the treatment of H2S donors. Taken together our data highlights a novel signaling axis that mechanistically links CBS with mitochondrial function and ER-mitochondrial tethering and could be considered as a new therapeutic approach for the intervention of EC dysfunction-related pathologies.
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