Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

Abstract

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.

Keywords: cell death; inflammation; ischemic reperfusion; ischemic stroke; mitochondrial fission; mitochondrial fusion; mitochondrial transfer; mitophagy.

Figure 1

Schematic representation of mitochondrial dysfunctions involved in the ischemic stroke (IS) pathophysiology. The blockage of artery leads to the instauration of two regions, an ischemic core in which necrosis takes over followed by the release of intracellular content, and a penumbra, a reversible damaged area where mitochondrial dysfunctions (1 magenta circle) activate several responses from apoptosis (2 magenta circles) to inflammation (3 magenta circle). Red squares highlight the therapeutic approaches and drugs that improved the ischemic outcome (OE: overexpression; CL: cardiolipin; KO: Knockout). All of the cellular pathways involved in the IS pathophysiology and approaches to overcome mitochondrial damage are widely described in the main text. Created with BioRender.com.

Figure 2

Mito-recovery in IS. Schematic representation of the mitochondrial mechanisms involved in the mito-recovery process during IS. In the red encircled boxes are indicated the therapeutic approaches and/or therapeutic drugs that affects each of the represented pathway (OE: overexpression). Created with BioRender.com (accessed on 8 February 2021).