Ischemic Stroke Risk Associated with Mitochondrial Haplogroup F in the Asian Population

Abstract

Mitochondrial dysfunction is involved in the pathogenesis of atherosclerosis, the primary risk factor for ischemic stroke. This study aims to explore the role of mitochondrial genomic variations in ischemic stroke, and to uncover the nuclear genes involved in this relationship. Eight hundred and thirty Taiwanese patients with a history of ischemic stroke and 966 normal controls were genotyped for their mitochondrial haplogroup (Mthapg). Cytoplasmic hybrid cells (cybrids) harboring different Mthapgs were used to observe functional differences under hypoxia-ischemia. RNA sequencing (RNASeq) was conducted to identify the particularly elevated mRNA. The patient study identified an association between Mthapg F1 and risk of ischemic stroke (OR 1.72:1.27–2.34, p = 0.001). The cellular study further demonstrated an impeded induction of hypoxic inducible factor 1α in the Mthapg F1 cybrid after hypoxia-ischemia. Additionally, the study demonstrated that Mthapg F cybrids were associated with an altered mitochondrial function, including decreased oxygen consumption, higher mitochondrial ROS production, and lower mitochondrial membrane potential. Mthapg F cybrids were also noted to be prone to inflammation, with increased expression of several inflammatory cytokines and elevated matrix metalloproteinase 9. The RNASeq identified significantly elevated expressions of angiopoietin-like 4 in Mthapg F1 cybrids after hypoxia-ischemia. Our study demonstrates an association between Mthapg F and susceptibility to ischemic stroke.

Emerging Role of Ferroptosis in the Pathogenesis of Ischemic Stroke: A New Therapeutic Target?

“…The production of ROS in mitochondria can depend on mitochondrial gene expression. Using RNA sequencing, it was shown that the mitochondrial haplogroup F1 (Mthapg F1)-encoding gene was overexpressed in patients with ischemic stroke and that Mthapg F1 upregulation induced ROS production in mitochondria and decreased cell viability ( Tsai et al, 2020 ). NADPH oxidase 2 (NOX2) is considered an important enzyme catalyzing ROS formation in the brain.…”

Ferroptosis Signaling and Regulators in Atherosclerosis

“…In studying the role of TAZ in ferroptosis in ovarian cancer, angiopoietin like 4 was found to be a direct target gene regulated by TAZ, sensitizing ferroptosis through activation of NOX2 ( Yang et al, 2020b ). More importantly, ANGPTL4 maintains the integrity of the vascular endothelium by regulating vascular permeability, angiogenesis, inflammatory signaling, oxidative stress and lipid metabolism ( Guo et al, 2014 ; Tsai et al, 2020 ). In addition, ANGPTL4 also regulates cellular energy homeostasis and reactive oxygen species and has been implicated in the pathogenesis of AS, including endothelial dysfunction, LDL oxidation and nitric oxide reduction ( Zhu et al, 2012 ; Tsai et al, 2020 ).…”

“…More importantly, ANGPTL4 maintains the integrity of the vascular endothelium by regulating vascular permeability, angiogenesis, inflammatory signaling, oxidative stress and lipid metabolism ( Guo et al, 2014 ; Tsai et al, 2020 ). In addition, ANGPTL4 also regulates cellular energy homeostasis and reactive oxygen species and has been implicated in the pathogenesis of AS, including endothelial dysfunction, LDL oxidation and nitric oxide reduction ( Zhu et al, 2012 ; Tsai et al, 2020 ). Hepatic ANGPTL4 deficiency significantly reduces triacylglycerol (TAG) and cholesterol levels, providing some protection against AS ( Singh et al, 2021 ).…”

Quality Matters? The Involvement of Mitochondrial Quality Control in Cardiovascular Disease

“…Our group has reported that the haplotype B4 (carrying the T16189C variant) is associated with T2DM (odds ratio [OR], 1.54 [95% CI 1.18–2.02]; P < 0.001) in the Chinese population, whereas subjects harboring haplogroup D4 have borderline resistance against DM generation (0.68 [0.49–0.94]; P = 0.02) ( Liou et al, 2010 ). Recently, a patient study with 830 Taiwanese ischemic stroke patients and 966 normal controls revealed an association between mitochondrial haplogroup F1 and risk of ischemic stroke (OR 1.72:1.27–2.34, p = 0.001) ( Tsai et al, 2020 ). In the same study, with the usage of a hybrid technique, Tsai et al (2020) demonstrated that mitochondrial haplogroup F1 cybrids were associated with decreased oxygen consumption, higher mitochondrial ROS production, and lower mitochondrial membrane potential.…”

“…Recently, a patient study with 830 Taiwanese ischemic stroke patients and 966 normal controls revealed an association between mitochondrial haplogroup F1 and risk of ischemic stroke (OR 1.72:1.27–2.34, p = 0.001) ( Tsai et al, 2020 ). In the same study, with the usage of a hybrid technique, Tsai et al (2020) demonstrated that mitochondrial haplogroup F1 cybrids were associated with decreased oxygen consumption, higher mitochondrial ROS production, and lower mitochondrial membrane potential. These cybrids were also noted to be prone to inflammation, with increased expression of several inflammatory cytokines.…”