USP10 deubiquitinates NDUFS1 at lysine 621 to stabilize mitochondrial function, and USP10 overexpression counteracts Ang II-induced atrial remodeling and reduces atrial fibrillation susceptibility.
USP10 is downregulated in atrial tissues from both AF mouse models and human AF patients.
USP10 overexpression counteracts Ang II-induced atrial remodeling and reduces AF susceptibility in a mouse model.
USP10 contributes to the restoration of mitochondrial function in the context of atrial fibrillation.
USP10 mechanistically deubiquitinates NDUFS1 at lysine 621, stabilizing NDUFS1 protein levels and mitigating Ang II-induced mitochondrial dysfunction.
USP10 influences calcium handling and triggered activity in atrial cells.
Atrial fibrillation (AF) is a common heart rhythm disorder that increases the risk of stroke and heart failure. This research investigated a protein called USP10, which belongs to a family of enzymes that regulate how other proteins are tagged for destruction within cells. The study found that USP10 levels are reduced in heart tissue from both mice with experimentally induced AF and human AF patients. When USP10 was artificially increased in mice, it protected the heart's upper chambers (atria) from the damaging structural and electrical changes that promote AF, and it made the mice less likely to develop AF. The researchers discovered that USP10 works by protecting another protein called NDUFS1, which is a critical component of the mitochondria — the energy-producing machinery inside cells. In AF, NDUFS1 gets tagged with a molecular 'destroy' signal (ubiquitin) at a specific location on the protein (lysine 621), leading to its breakdown and subsequent mitochondrial dysfunction. USP10 acts as a 'rescue' enzyme that removes this destroy tag, keeping NDUFS1 stable and mitochondria functioning properly. The study also showed USP10 affects how heart cells handle calcium, which is important for normal electrical signaling in the heart. This research suggests that boosting USP10 activity or finding ways to prevent NDUFS1 from being degraded could represent a new therapeutic approach for treating or preventing AF. By targeting this specific molecular pathway — rather than directly suppressing electrical activity as current drugs do — future treatments might address underlying causes of AF while potentially reducing the cardiovascular risks associated with the condition.
Fu W, Tian X, Zhou J, Huang Y, Li H, Wang Z, et al.. (2026). USP10 mitigates Ang II-induced atrial remodeling and atrial fibrillation susceptibility by deubiquitinating NDUFS1.. JCI insight. https://doi.org/10.1172/jci.insight.195761