Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities

Abstract

Mitochondrial dysfunction characterized by impaired bioenergetics, oxidative stress and aldehydic load is a hallmark of heart failure. Recently, different research groups have provided evidence that selective activation of mitochondrial detoxifying systems that counteract excessive accumulation of ROS, RNS and reactive aldehydes is sufficient to stop cardiac degeneration upon chronic stress, such as heart failure. Therefore, pharmacological and non-pharmacological approaches targeting mitochondria detoxification may play a critical role in the prevention or treatment of heart failure. In this review we discuss the most recent findings on the central role of mitochondrial dysfunction, oxidative stress and aldehydic load in heart failure, highlighting the most recent preclinical and clinical studies using mitochondria-targeted molecules and exercise training as effective tools against heart failure.

Stress-mediated generation of deleterious ROS in healthy individuals - role of cytochrome c oxidase

“…In the sequence of reactions between stress and multiple diseases, shown in Fig. 1, the step between the increase of cytosolic Ca 2+ and hyperpolarization of ΔΨ m was so far unknown in the current literature [5,6,92]. The above-reviewed data explains how stress could induce excessive production of ROS in mitochondria by switching off the allosteric ATP inhibition of COX, which under relaxed conditions, keeps ΔΨ m at low values (below 130 mV).…”

“…In a multi-cohort study involving 90,164 individuals, the risk of coronary heart disease was 41% higher in individuals with the two work stressors effort-reward imbalance and job strain [2]. Although the molecular basis of these diseases is very complex, the role of oxidative distress [3], in particular increased reactive oxygen species (ROS) production in mitochondria, seems to predominate [4][5][6][7]. Furthermore, multiple other diseases like cancer, hypertension, atherosclerosis, ischemia/reperfusion injury, neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, rheumatoid arthritis, diabetes mellitus, and mitochondrial diseases have also been related to excessive ROS production in cells [8][9][10][11].…”

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

“…Nevertheless, the results available to date position mitochondria as likely therapeutic targets for treatment of such diseases as cancer, chronic inflammatory states, and atherosclerosis. Selective mitochondria-targeting drugs, such as mitochondrial antioxidants, are being tested in preclinical and clinical trials [151,152]. Moreover, certain mtDNA mutations are being currently explored as diagnostic markers [152].…”

Bone marrow stromal cells induce an ALDH+stem cell-like phenotype in AML cells through TGF-β-p38-ALDH2 pathway

“…ALDH plays a prominent role in several diseases and malignancies (18,29), and specific ALDH inhibitors with potentially anti-tumor effects have been developed (17,26,(30)(31)(32). In this study, we examined the role of ALDH2 inhibitors in counteracting the stem-like phenotype and chemotherapy resistance acquired by AML cells in the presence of stromal cells.…”