Abstract
The adaptation of mitochondrial homeostasis to ischemic injury is not fully understood. Here, we studied the role of dynamin-related protein 1 (Drp1) in this process. We found that mitochondrial morphology was altered in the early stage of ischemic injury while mitochondrial dysfunction occurred in the late stage of ischemia. Drp1 appeared to inhibit mitophagy by upregulating mito-Clec16a, which suppressed mito-Parkin recruitment and subsequently impaired the formation of autophagosomes in vascular tissues after ischemic injury. Moreover, ischemia-induced Drp1 activation enhanced apoptosis through inducing mitochondrial translocation of BAX and thereby increasing release of Cytochrome C to activate caspase-3/-9 signalling. Furthermore, Drp1 mediated metabolic disorders and inhibited the levels of mitochondrial glutathione to impair free radical scavenging, leading to further increases in ROS and the exacerbation of mitochondrial dysfunction after ischemic injury. Together, our data suggest a critical role for Drp1 in ischemic injury.
Highlights
Ischemia, a condition marked by insufficient blood supply to tissues[1], hallmarks haemorrhagic shock[2], myocardial infarction, stroke[3], and tumorigenesis[4]
Mitochondrial dysfunction is closely related to autophagy, apoptosis, and metabolism after ischemic injury
To examine whether mitochondrial dysfunction may occur in the late stage of ischaemic injury, we studied the variations in mitochondrial function after hypoxia treatment in vascular smooth muscle cell line (VSMC) at different time points
Summary
A condition marked by insufficient blood supply to tissues[1], hallmarks haemorrhagic shock[2], myocardial infarction, stroke[3], and tumorigenesis[4]. The extent of tissue injury is associated with the extent of oxygen deprivation and the duration of the ischemic period[5]. Vascular hyporeactivity with a progressive decrease in blood pressure may cause multiple organ dysfunction, and even death[7]. Mitochondria are a major target in hypoxic/ischaemic injury, while increasing mitochondrial damage occurs with prolonged ischemic duration[8], which in turn compromises cellular bioenergetics[9]. Whether the perturbation of mitochondrial homeostasis and cellular energetics in the vascular system occurs in a timedependent manner after ischemic injury remains unknown
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