Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies

Abstract

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].

Keywords: Mdivi-1; apoptosis; ischemia-reperfusion injury; mitochondrial function; stroke.

FIGURE 1

PRISMA flow chart for study selection protocol (2020 version).

FIGURE 2

The hypothesized diagram. The figure provides the mechanisms of ischemia/reperfusion (I/R) injury in the brain after ischemic stroke, as well as the therapeutic effects of Mdivi-1 on neural mitochondria functions and neural mitochondria-mediated apoptosis. I/R injury is shown to induce neural mitochondrial respiration deficiency, as evidenced by decreases in mitochondrial membrane potential (ΔΨm), ATP production, and neural mitochondrial complexes I–IV. In addition, I/R injury could dysregulate neural mitochondrial quality-control, as evidenced by increases in neural mitochondrial biogenesis regulators (e.g., PGC-1α, TFAM, and NRF-1) as a compensatory response to the reduction of mitochondrial content including mitochondrial DNA (mtDNA), as well as increases in mitochondrial fission (Drp-1) and neural mitophagy. Neural mitochondrial respiratory deficiency and neural mitochondrial quality-control dysregulation in I/R injury promote neural mitochondria-mediated apoptosis, as evidenced by the activation of apoptotic factors, including mitochondria-mediated caspase-independent apoptotic factors (e.g., AIF), mitochondria-mediated caspase-dependent upstream proapoptotic factors (e.g., Bax), and mitochondria-mediated caspase-dependent upstream proapoptotic factors (e.g., cytochrome c, caspase-9, and caspase-3), as well as the inactivation of antiapoptotic factors (e.g., Bcl-2). The included studies suggest that Mdivi-1 could restore mitochondrial membrane potential (ΔΨm), enhance ATP production and normalize neural mitochondrial complexes I-V, suggesting that Mdivi-1 could attenuate neural mitochondrial respiratory deficiency against I/R injury after ischemic stroke. In addition, Mdivi-1 has been shown to further enhance biogenesis regulators (e.g., PGC-1α, TFAM, and NRF-1) to increase mtDNA, inactivate mitochondrial fission factor (Drp-1), and suppress neural mitophagy, implying that Mdivi-1 could protect neural mitochondria quality-control against I/R injury. As a result, Mdivi-1 attenuates neural mitochondria-mediated apoptosis, which is supported by the reductions in proapoptotic factors (e.g., AIF, Bax, cytochrome c, caspase-9, and caspase-3) as well as the increases in antiapoptotic factors (e.g., Bcl-2).