The Imbalance of Mitochondrial Fusion/Fission Drives High-Glucose-Induced Vascular Injury

Abstract

Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially in the early stage of hyperglycemia. The in vitro results show that persistent cellular apoptosis and endothelial dysfunction can be induced rapidly within 12 hours’ high-glucose pre-incubation. Our results show that mitochondria maintain normal morphology and function within 4 hours’ high-glucose pre-incubation; with the extended high-glucose exposure, there is a transition to progressive fragmentation; once severe mitochondria fusion/fission imbalance occurs, persistent cellular apoptosis will develop. In vitro and in vivo results consistently suggest that mitochondrial fusion/fission homeostasis alterations trigger high-glucose-induced vascular injury. As the guardian of mitochondria, AMPK is suppressed in response to hyperglycemia, resulting in imbalanced mitochondrial fusion/fission, which can be reversed by AMPK stimulation. Our results suggest that mitochondrial fusion/fission’s staged homeostasis may be a predictive factor of diabetic cardiovascular complications.

Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission

“…Notably, mitochondrial fission is essential for excessive mtROS production induced by high glucose. [ 80 ] Mitochondria undergo rapid fragmentation, upregulate fission-associated proteins, dynamin-related protein 1 (Drp1) and Fis1 expressions, and increase mtROS production [ 81 ] Remarkably, metformin also inhibits Drp1 -mediated mitochondrial fission to protect adipose tissue from oxidative damage induced by high-glucose environment [ 82 ] The dual-loaded hydrogel effectively reduced ROS production in tissues and cells. However, it remains unknown whether the action mechanism of this hydrogel is associated with mitochondrial dynamic and whether it can reduce ROS production by relieving mitochondrial fission.…”

“…The primary characteristic of these wounds is increased levels of reactive oxygen species (ROS) due to persistent hyperglycemia, inducing excessive oxidative stress and impaired antioxidant capacity [ 4 ] and causing microvascular injury, angiogenesis inhibition, and prolonged inflammatory response [ 5 ]. Reportedly, mitochondrial dynamics, particularly mitochondrial fission, have been strongly associated with hyperglycemia-induced ROS formation and vascular damage [ [6] , [7] , [8] , [9] ], disrupting cell integrity and barrier function and delaying neovascularization [ 10 , 11 ].…”

Homoplantaginin attenuates high glucose‐induced vascular endothelial cell apoptosis through promoting autophagy via the AMPK/TFEB pathway

“…Hyperglycaemia can induce inflammation, promote intracellular oxidative stress, destroy cellular homeostasis, lead to cell apoptosis, and cause vascular endothelial dysfunction (Paneni et al, 2015; Wasserman et al, 2018; Zheng et al, 2021). Apoptosis is regulated by apoptosis‐related factor‐1, Cyt.c, caspase family, and Bcl‐2 family.…”

Mitochondrial dynamics in vascular remodeling and target-organ damage

“…A recent study showed that mitochondrial fission genes Fis1 and Drp1 were overexpressed under HG conditions, and that downregulation of Fis1 and Drp1 preserved the normal morphology of mitochondria, inhibited mitochondrial fission, and reduced apoptosis in retinal endothelial cells ( 102 ). Emerging evidence suggests that altered mitochondrial fusion-fission homeostasis is divided into a compensatory phase, an equilibrium shift phase, and a loss of compensatory phase ( 103 ). Initially, Mfn1 and Mfn2 exhibit a significant decrease while Drp1 and Fis1 are elevated, and mitochondrial fusion/fission homeostasis is disturbed, but normal mitochondrial membrane potential (MMP) can still be maintained.…”

“…Then, with prolonged high glucose exposure, mitochondrial fusion/fission imbalance and mitochondrial fragmentation occurred. Finally, Opa1 expression decreased and mitochondrial fragmentation triggered endothelial cell apoptosis ( 103 ). Notably, Fis1 expression initially increased and decreased at the end, so Fis1 may be a predictor of changes in mitochondrial fusion-fission homeostasis during vascular injury.…”