Mitochondria in Health and Diseases

Mitochondria have been recognized as the “power plants” that provide over 90% of ATP required for cell metabolism. Also, they are engaged in other aspects of cell metabolism and function and participate in the regulation of ion homeostasis, cell growth, redox status, cell signaling, and, thus, play a pivotal role in both cell survival and cell death mechanisms. Due to their central role in cell life and death, mitochondria are also involved in the pathogenesis and progression of numerous human diseases, including, among others, cancer, neurodegenerative and cardiovascular disorders, diabetes, traumatic brain injury, and inflammation.

Mitochondria involvement in these diseases has been attributed to the pivotal role the organelle plays in the sequelae of events that culminate in cell death through various programmed (apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy) and non-programmed (necrosis) cell death mechanisms. A growing body of evidence on the important role of mitochondria under physiological conditions and human diseases is associated with increased number of biomedical studies in mitochondrial research.

Since 2010, the number of mitochondria-related publications has exceeded other organelles including the nucleus, endo(sarco)plasmic reticulum, and the Golgi apparatus. Increased attention to mitochondria in recent decades stimulated preclinical studies on various cell and animal models to elucidate mitochondria as a therapeutic target for the treatment of a broad spectrum of human diseases. A large number of preclinical studies demonstrated beneficial effects of various pharmacological agents targeting mitochondrial ion channels, electron transfer chain (ETC), oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle, reactive oxygen species (ROS) production, permeability transition pore, DNA, membrane integrity, and apoptotic proteins, among others.

Mitochondria in Health

This section of the Editorial focuses on the role of mitochondria in maintaining normal and healthy physiology. In this endeavor, 13 articles (10 original research and 3 review articles) elucidating different aspects of mitochondria in maintaining health in the organism have been published. These studies can be grouped in the following four sections: Mitochondrial homeostasis, Mitochondrial and cellular metabolism,Crosstalk between mitochondria and other subcellular compartments, and Mitochondrial ion channels.

The review articles highlight the significance of mitochondria crosstalk with cytoskeletal proteins key in normal mitochondrial and cellular physiology, mitochondrial gene regulation in different cellular contexts, and the importance of emerging aspects of mitochondrial transcripts and gene regulation in human health and disease, and (c) the role of telomeres and telomerase in cardiac aging. Altogether, these seminal articles provide a broad spectrum of new and unique perspectives in our understanding of the role of mitochondria in health and disease.

Mitochondrial homeostasis

To preserve themself and the host cell, mitochondria must maintain a balance between mitochondrial proliferation (biogenesis) and degradation (mitophagy). To mitigate degradation, mitochondria rely on intrinsic strategies to maintain quality. In this effort, Hur et al. explored a novel role of HtrA2/OMI, a serine protease, in the regulation of mitochondrial homeostasis during hepatic fibrogenesis. The authors showed that overexpression of HtrA2/OMI led to antifibrotic effect due to CCl4, by enhancing the antioxidant activity of mitochondria in hepatocytes.

In an unrelated study, but with a similar focus on mitochondria self-preservation during stress due to excess of Ca2+, Mishra et al. reported an intriguing observation that cyclosporin A bolsters mitochondrial Ca2+ buffering capacity in a phosphate-dependent manner in guinea pig cardiomyocytes isolated mitochondria. This novel observation indicates that cyclosporin A activates, yet determined, mitochondrial molecular mechanisms involved in Ca2+ sequestration. This additional insight into the action of cyclosporin A could potentially reveal different therapeutic approaches targeted at regulating mitochondria Ca2+ homeostasis and reduce cardiac injury in Ca2+ overload.

Mitochondrial and cellular metabolism

Normal mitochondrial and cellular metabolisms are tightly coupled. In healthy conditions, mitochondria account for the majority of the ATP produced in the cell via OXPHOS. In healthy cardiomyocytes, most of the acetyl CoA consumed by the heart is from fatty acids, with the remainder from pyruvate. In their study, Toleikis et al., investigated the effects of fatty acid oxidation-induced changes in mitochondrial morphology and conformational changes in adenine nucleotide translocase (ANT) on the kinetics of the regulation of mitochondrial respiration in rat skinned cardiac fibers.

Fatty acids alone or in combination with pyruvic acid was the substrate. The key message from this study is that fatty acids could regulate cellular energy metabolism by increasing the affinity of the ADP/ATP transporter for ADP, via conformational changes of the transporter. This study provides new understandings of the metabolic changes in altered age-related cardiovascular diseases. In another study, Parodi-Rullán et al.sought to elucidate whether ANT knockdown affects respiratory chain supercomplex formation in H9c2 cardiomyoblasts.

This study is predicated on a previous observation by the same group that pharmacological inhibition of ANT disintegrated respirasome, the main respiratory chain supercomplex containing ETC complexes I, III, and IV, in cardiac mitochondria suggesting an essential role of ANT in respirasome formation. ANT1 knockdown in the H9c2 cells reduced the ∆Ψm but increased total cellular ATP levels. Furthermore, ANT1 downregulation did not alter the enzymatic activity of the ETC complexes I-IV but reduced the level of the respirasome.

Mitochondria in Diseases

Recently, different aspects of mitochondrial dysfunction have been associated with multiple human diseases, and hence, mitochondria are becoming a promising pharmacological target for the treatment of a broad range of diseases. This section of the Editorial comprising 11 articles focuses on the role of mitochondrial dysfunction in several pathological conditions. These studies can be grouped in the following four sections based on disease types: Neurological disorders, Liver diseases, Diseases associated with oxygen deficiency, and Inborn and metabolic diseases.

Neurological disorders

Described a novel mechanism potentially regulating mitochondrial dynamics and seizure activity in the central nervous system. They provide novel evidence that transient receptor potential canonical channel-6 (TRPC6) regulates mitochondrial Lon protease 1 (LONP1) expression via the ERK1/2-mediated pathway. Activation of this pathway dramatically changes mitochondrial dynamics and assumed as an important therapeutic target for neuroprotection from various neurological diseases.

In another study, the same group of authors [17] demonstrated that 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me), an analog of oleanolic acid exhibiting promising therapeutic effects in cancer, inflammatory, and neural diseases, irreversibly inhibits Lon protease-1 (LONP1) and activates ERK1/2 and c-Jun N-terminal kinase (JNK) pathways. They showed that CDDO-Me may selectively attenuate seizure activity in the cornu ammonis area 1 by rescuing the abnormal mitochondrial machinery, but in contrast to data reported above, this pathway was independent of LONP1 activity.

Liver diseases

A study by Tan et al.investigated the impact of lipid droplet accumulation on cellular oxidative stress. They have shown that overexpression of Perilipin 5 (PLIN5), a key lipid droplet protein required for the formation of contacts between mitochondria and lipid droplets, reduces ROS levels and improves mitochondrial function in HepG2 cells. They assume that the upregulation of PLIN5 is a survival strategy of cells in response to stress.

Feichtinger et al.examined cholangiocellular carcinoma biopsies in order to better understand the impact of mitochondria. They have found that the expression of voltage-dependent anion-selective channel 1 (VDAC-1) in the outer mitochondrial membrane inversely correlates with UICC (Union Internationale Contre le Cancer) cancer stage classification. Also, significantly lower survival was observed for low/moderate VDAC1 expressors compared to high expressors. These data suggest that lower mitochondrial mass is associated with shorter survival of patients with cholangiocellular carcinoma.

Diseases associated with oxygen deficiency

They reported the changes in cerebellar amino acid metabolism in pregnancy with particular emphasis on the role of 2-oxoglutarate dehydrogenase complex. Hormonal changes occurring in pregnancy are known to coordinate a broad range of physiological adaptations, including changes in amino acid metabolism. The data obtained by this group suggest that these changes critically influence mitochondrial function and the resistance of pregnant rats to hypoxia.

The authors suggest that specific patterns of amino acids and the activity of the α-ketoglutarate dehydrogenase complex in mitochondria can be used as sensitive markers for the adaptation to hypoxia. In a review article, Ferko et al. [23] summarized and discussed previous studies that evaluated the factors affecting the regulatory mechanisms in mitochondria at the level of mitochondrial permeability transition and its impact on comprehensive myocardial protection. The review put particular emphasis on signaling pathways leading to mitochondrial energy maintenance during partial oxygen deprivation.

Inborn and metabolic diseases

Leber’s hereditary optic neuropathy (LHON), an inherited mitochondrial disease, was the focus of the study. The authors performed an entire mtDNA genome sequencing and provided genealogical and molecular genetic data on mutations and haplogroup background of LHON patients in Russia (Siberia) and Europe. The results indicate that haplogroup affiliation and the mutational spectrum of the Western Siberian LHON cohort substantially deviated from those of European populations.

Was focused on the adverse effects of thiazolidinediones, a class of anti-diabetic drugs, which sometimes were associated with heart failure. The latter was not clear, because these drugs activate the peroxisome proliferator-activated receptor-gamma (PPARγ), which is believed to play a key role in cardioprotection. However, Riess and coauthors showed that there is another PPARγ-independent mechanism of thiazolidinedione action based on a reversible increase in mitochondrial oxidation, causing an increase in ROS production and a decrease in membrane potential. Both mechanisms may cause damage to the myocardium and have to be considered in the treatment of diabetic patients.

 

Author: Sabzali Javadov,Andrey V. Kozlov, Amadou KS Camara