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. 2021 Dec 24;14:778569. doi: 10.3389/fnmol.2021.778569

FIGURE 2.

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).