This systematic review sought to determine the effects of Mitochondrial division inhibitor-1 (Mdivi-1) on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in ischemia/reperfusion (I/R) injury after ischemic stroke. Pubmed, Web of Science, and EMBASE databases were searched through July 2021. The studies published in English language that mentioned the effects of Mdivi-1 on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in I/R-induced brain injury were included. The CAMARADES checklist (for in vivo studies) and the TOXRTOOL checklist (for in vitro studies) were used for study quality evaluation. Twelve studies were included (median CAMARADES score = 6; TOXRTOOL scores ranging from 16 to 18). All studies investigated neural mitochondrial functions, providing that Mdivi-1 attenuated the mitochondrial membrane potential dissipation, ATP depletion, and complexes I-V abnormalities; enhanced mitochondrial biogenesis, as well as inactivated mitochondrial fission and mitophagy in I/R-induced brain injury. Ten studies analyzed neural mitochondria-mediated apoptosis, showing that Mdivi-1 decreased the levels of mitochondria-mediated proapoptotic factors (AIF, Bax, cytochrome c, caspase-9, and caspase-3) and enhanced the level of antiapoptotic factor (Bcl-2) against I/R-induced brain injury. The findings suggest that Mdivi-1 can protect neural mitochondrial functions, thereby attenuating neural mitochondria-mediated apoptosis in I/R-induced brain injury. Our review supports Mdivi-1 as a potential therapeutic compound to reduce brain damage in ischemic stroke (PROSPERO protocol registration ID: CRD42020205808).Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020205808].

Neural mitochondrial dysfunction, neural oxidative stress, chronic neuroinflammation, toxic protein accumulation, and neural apoptosis are common causes of neurodegeneration. Elamipretide, a small mitochondrially-targeted tetrapeptide, exhibits therapeutic effects and safety in several mitochondria-related diseases. In neurodegeneration, extensive studies have shown that elamipretide enhanced mitochondrial respiration, activated neural mitochondrial biogenesis via mitochondrial biogenesis regulators (PCG-1α and TFAM) and the translocate factors (TOM-20), enhanced mitochondrial fusion (MNF-1, MNF-2, and OPA1), inhibited mitochondrial fission (Fis-1 and Drp-1), as well as increased mitophagy (autophagy of mitochondria). In addition, elamipretide has been shown to attenuate neural oxidative stress (hydrogen peroxide, lipid peroxidation, and ROS), neuroinflammation (TNF, IL-6, COX-2, iNOS, NLRP3, cleaved caspase-1, IL-1β, and IL-18), and toxic protein accumulation (Aβ). Consequently, elamipretide could prevent neural apoptosis (cytochrome c, Bax, caspase 9, and caspase 3) and enhance neural pro-survival (Bcl2, BDNF, and TrkB) in neurodegeneration. These findings suggest that elamipretide may prevent the progressive development of neurodegenerative diseases via enhancing mitochondrial respiration, mitochondrial biogenesis, mitochondrial fusion, and neural pro-survival pathway, as well as inhibiting mitochondrial fission, oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis. Elamipretide or mitochondrially-targeted peptide might be a targeted agent to attenuate neurodegenerative progression.