Diverse roles of mitochondria in ischemic stroke

Abstract

Stroke is the leading cause of adult disability and mortality in most developing and developed countries. The current best practices for patients with acute ischemic stroke include intravenous tissue plasminogen activator and endovascular thrombectomy for large-vessel occlusion to improve clinical outcomes. However, only a limited portion of patients receive thrombolytic therapy or endovascular treatment because the therapeutic time window after ischemic stroke is narrow. To address the current shortage of stroke management approaches, it is critical to identify new potential therapeutic targets. The mitochondrion is an often overlooked target for the clinical treatment of stroke. Early studies of mitochondria focused on their bioenergetic role; however, these organelles are now known to be important in a wide range of cellular functions and signaling events. This review aims to summarize the current knowledge on the mitochondrial molecular mechanisms underlying cerebral ischemia and involved in reactive oxygen species generation and scavenging, electron transport chain dysfunction, apoptosis, mitochondrial dynamics and biogenesis, and inflammation. A better understanding of the roles of mitochondria in ischemia-related neuronal death and protection may provide a rationale for the development of innovative therapeutic regimens for ischemic stroke and other stroke syndromes.

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

“…More than 87% of strokes are ischemic and caused by obstruction of one or more cerebral arteries [1]. An inadequate supply of oxygen and glucose results in an ischemic cascade involving mitochondrial [2] and endoplasmic reticulum (ER) [3] dysfunction.…”

“…The BCL-2 family has been categorized into 2 groups: anti-apoptotic proteins, including Bcl-2, Bcl-xL, and Bcl-w, and proapoptotic proteins, such as Bax, Bak, Bim, Bid, Bad, Noxa, and p53-upregulated modulator of apoptosis (PUMA) [16][17][18][19]. The pro-apoptotic BH3-only BCL-2 subfamily is known to be upregulated after cerebral ischemia [2,20].…”

Selective brain hypothermia ameliorates focal cerebral ischemia-reperfusion injury via inhibiting Fis1 in rats

“…Cerebral I/R injury is a common clinical pathophysiological phenomenon after restoring blood perfusion in stroke patients, which involves multiple pathogenesis [7]. Mitochondria reportedly play an important role in the development of I/R injury, which is involved in calcium homeostasis, oxidative phosphorylation, reactive oxygen species production, and apoptosis [13]. Recent studies have suggested that morphological changes in the mitochondria are relevant to I/R injury [8,22,23].…”

“…Apoptosis is considered a vital component of the development of cerebral I/R injury [30]. Excessive mitochondrial fission promotes mitochondrial outer membrane permeability and increases Cyto c release, subsequently activating the apoptotic cascade reaction and eventually aggravating neurological damage [13,31]. Moreover, in a study by Wang et al [32], adenoviral Fis1, which can induce Fis1 overexpression, increased mitochondrial fission and apoptosis, whereas Fis1 knockdown attenuated mitochondrial fission and apoptosis.…”

“…Within the cell, mitochondria exist in an ever-changing dynamic state—constant fission and fusion—to form mitochondrial networks and maintain cellular physiological function and survival [10]. Notably, growing evidence has indicated that I/R injury can break this balance to induce neuronal apoptosis [11–13]. Mitochondrial fission protein 1 (Fis1), a 16-kDa protein anchored to the outer membrane of the mitochondria, mediates mitochondrial fission by recruiting cytoplasmic dynamin-related protein1 (Drp1) into the mitochondrial outer membrane [14].…”