Role Of Mitochondrial Dysfunction Research Articles

Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients

Hexanucleotide repeat expansion in C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Loss of C9ORF72 protein function and a toxic gain-of-function directly by the RNA or RAN translation have been proposed as triggering pathological mechanisms, along with the accumulation of TDP-43 protein. In addition, mitochondrial defects have been described to be a major driver of disease initiation. Mitochondrial DNA copy number has been proposed as a useful biomarker of mitochondrial dysfunction. The aim of our study was to determine the presence of mtDNA copy number alterations in C9ALS/FTD patients. Therefore, we assessed mtDNA copy number in postmortem prefrontal cortex from 18 C9ORF72 brain donors and 9 controls using digital droplet PCR. A statistically significant decrease of 50% was obtained when comparing C9ORF72 samples and controls. This decrease was independent of age and sex. The reduction of mtDNA copy number was found to be higher in patients' samples presenting abundant TDP-43 protein inclusions. A growing number of studies demonstrated the influence of mtDNA copy number reduction on neurodegeneration. Our results provide new insights into the role of mitochondrial dysfunction in the pathogenesis of C9ALS/FTD.

The Roles of Mitochondrial Dysfunction and Reactive Oxygen Species in Aging and Senescence.

The aging process deteriorates organs' function at different levels, causing its progressive decline to resist stress, damage, and disease. In addition to alterations in metabolic control and gene expression, the rate of aging has been connected with the generation of high amounts of Reactive Oxygen Species (ROS). The essential perspective in free radical biology is that reactive oxygen species (ROS) and free radicals are toxic, mostly cause direct biological damage to targets, and are thus a major cause of oxidative stress. Different enzymatic and non-enzymatic compounds in the cells have roles in neutralizing this toxicity. Oxidative damage in aging is mostly high in particular molecular targets, such as mitochondrial DNA and aconitase, and oxidative stress in mitochondria can cause tissue aging across intrinsic apoptosis. Mitochondria's function and morphology are impaired through aging, following a decrease in the membrane potential by an increase in peroxide generation and size of the organelles. Telomeres may be the significant trigger of replicative senescence. Oxidative stress accelerates telomere loss, whereas antioxidants slow it down. Oxidative stress is a crucial modulator of telomere shortening, and that telomere-driven replicative senescence is mainly a stress response. The age-linked mitochondrial DNA mutation and protein dysfunction aggregate in some organs like the brain and skeletal muscle, thus contributing considerably to these post-mitotic tissues' aging. The aging process is mostly due to accumulated damage done by harmful species in some macromolecules such proteins, DNA, and lipids. The degradation of non-functional, oxidized proteins is a crucial part of the antioxidant defenses of cells, in which the clearance of these proteins occurs through autophagy in the cells, which is known as mitophagy for mitochondria.

Mitochondrial Dysfunction Associated with Low Expression of Bcl-2: an Inflammatory Mediator in Diabetic Patients with Atherosclerosis

Objective: To investigate mitochondrial dysfunction and pattern of expression of B-cell lymphoma 2 (Bcl-2) and correlate these with cardiovascular diseases (CVD) in type 2 diabetes mellitus (T2DM).   Background: Diabetes mellitus (DM) raises the risk of CVD, which contributes significantly to the high mortality rates associated with the disease. The role of mitochondrial dysfunction and apoptosis in the development of CVD has been suggested, however the mechanisms involved are unknown.   Methods: Type 2 diabetic mellitus patients with atherosclerosis (T2DM + ATHER, n=40), T2DM patients (n=40) and a control group of age-matched non-diabetic individuals (n=35) were enrolled in this study. Blood samples were collected and analysed for the presence of anti-apoptotic-related factors, Bcl-2 in Peripheral mononuclear cells by qPCR as well as mitochondrial dysfunction by immunofluorescence analysis. Serum TNF-α and antioxidant enzymes (SOD) were measured by ELISA.   Result: Bcl-2 expression was significantly decreased in patients with T2DM + ATHER and T2DM (P < 0.05) compared to the control group. MitoSpy Red staining revealed nuclear condensation and fragmentation in T2DM + ATHER and T2DM. There was a significant increase in pro-inflammatory cytokine TNF-α while the levels of SOD were significantly decreased in the T2DM + ATHER and T2DM patient group (P<0.05) compared to the control group.   Conclusion: These results suggest that mitochondrial dysfunction was associated with oxidative stress and inflammation in patients with T2DM +ATHER.

Molecular targets regulating endoplasmic reticulum-mitochondria crosstalk for NAFLD treatment

Non-alcoholic fatty liver disease (NAFLD) as the most common chronic liver disease poses a significant impact on public healthcare and economic risk worldwide. As a multifactorial disease, NAFLD is usually associated with many comorbidities such as obesity, insulin resistance, hypertension, hyperlipidemia, diabetes, and cardiovascular disease. Without effectively preventive intervention, the advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). However, there is no approved therapeutic treatment. Excessive fat accumulation in the liver is the hallmark of NAFLD, which can lead to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Dysfunction of two organelles also induces the upregulation of reactive oxygen species (ROS), activation of the unfolded protein response (UPR), and disruption of calcium transport, which promote NAFLD progression. Herein, this review summarized the current understanding of the roles of mitochondrial dysfunction and ER stress in the pathogenesis of NAFLD. Specifically, this review focused on the key molecules associated with the ER-mitochondria communication and different treatment options by targeting ER stress and mitochondrial dysfunction to treat NAFLD or NASH. Clinical trials to evaluate the therapeutic efficacy of representative agents, such as natural products, metabolites, and modulators of stress, have been reviewed and analyzed. Overall, recent findings suggest that targeting ER stress and mitochondrial dysfunction holds a promise for NAFLD treatment.

Targeting α-synuclein aggregation and its role in mitochondrial dysfunction in Parkinson's disease.

Lewy bodies that contain aggregated α-synuclein in dopamine neurons are the main culprit for neurodegeneration in Parkinson's disease. However, mitochondrial dysfunction has a well-established and prominent role in the pathogenesis of Parkinson's disease. The exact mechanism by which α-synuclein causes dopamine neuronal loss is unclear. Recent evidence suggests that aggregated α-synuclein localises in the mitochondria contributes to oxidative stress-mediated apoptosis in neurons. Therefore, the involvement of aggregated α-synuclein in mitochondrial dysfunction-mediated neuronal loss has made it an emerging drug target for the treatment of Parkinson's disease. However, the exact mechanism by which α-synuclein permeabilises through the mitochondrial membrane and affects the electron transport chain remains under investigation. In the present study, we describe mitochondria-α-synuclein interactions and how α-synuclein aggregation modulates mitochondrial homeostasis in Parkinson's disease pathogenesis. We also discuss recent therapeutic interventions targeting α-synuclein aggregation that may help researchers to design novel therapeutic treatments for Parkinson's disease.

The Role of Mitochondria Dysfunction in Inflammatory Bowel Diseases and Colorectal Cancer.

Inflammatory bowel disease (IBD) is one of the leading gut chronic inflammation disorders, especially prevalent in Western countries. Recent research suggests that mitochondria play a crucial role in IBD development and progression to the more severe disease—colorectal cancer (CRC). In this review, we focus on the role of mitochondrial mutations and dysfunctions in IBD and CRC. In addition, main mitochondria-related molecular pathways involved in IBD to CRC transition are discussed. Additionally, recent publications dedicated to mitochondria-targeted therapeutic approaches to cure IBD and prevent CRC progression are discussed.

KCa3.1 in diabetic kidney disease.

Diabetic kidney disease (DKD) is a significant health concern. Innovative strategies to prevent or limit the progression of DKD are urgently needed due to the limitation of existing treatments. KCa3.1, a potassium channel, is involved in a range of biological processes from cell survival to cell death. This review summarizes the current knowledge on the pathophysiological functions of the KCa3.1 channel, specifically its involvement in maintaining mitochondrial function. More specifically, the therapeutic potential of targeting KCa3.1 in DKD is systematically discussed in the review. Mitochondrial dysfunction contributes to the development and progression of DKD. Accumulating evidence indicates that KCa3.1 dysregulation plays a crucial role in mitochondrial dysfunction, in addition to driving cellular activation, proliferation and inflammation. Recent studies demonstrate that KCa3.1 deficiency improves diabetes-induced mitochondrial dysfunction in DKD, which is attributed to modulation of mitochondrial quality control through mitigating the altered mitochondrial dynamics and restoring abnormal BNIP3-mediated mitophagy. Based on its role in fibrosis, inflammation and mitochondrial dysfunction, pharmacological inhibition of KCa3.1 may offer a promising alternative for the treatment of DKD. Due to its safety profile in humans, the repurposing of senicapoc has the potential to expedite an urgently needed new drug in DKD.

Mitochondrial bioenergetics and D-ribose in HFpEF: a brief narrative review.

ObjectiveIn this review article, we briefly describe the status of treatment options for HFpEF and the role of mitochondrial dysfunction in the pathogenesis of HFpEF as an alternative therapeutic target. We also examine the mechanisms of D-ribose in cellular energy production and discuss the potential disadvantages and benefits of supplemental use of D-ribose in patients with HFpEF.BackgroundHeart failure is a major cardiovascular disease that impacts over 6 million Americans and is one of the leading causes for morbidity and mortality. Patients with heart failure often experience shortness of breath and fatigue along with impaired physical capacity, all leading to poor quality of life. As a subtype of heart failure, heart failure with preserved ejection fraction (HFpEF) is characterized with impaired diastolic function. Currently, there are no effective treatments specifically for HFpEF, thus clinicians and researchers are searching for therapies to improve cardiac function. Emerging evidence indicate that mitochondrial dysfunction and impaired cardiac bioenergetics are among the underlying mechanisms for HFpEF. There is increased interest in investigating the use of supplements such as D-ribose to enhance mitochondrial function and improve production of adenosine triphosphate (ATP).MethodsFor this narrative review, more than 100 relevant scientific articles were considered from various databases (e.g., PubMed, Web of Science, CINAHL, and Google Scholar) using the keywords “Heart Failure”, “HFpEF”, “D-ribose”, “ATP”, “Mitochondria”, Bioenergetics”, and “Cellular Respiration”.ConclusionsIt is essential to find potential targeted therapeutic treatments for HFpEF. Since there is evidence that the HFpEF is related to impaired myocardial bioenergetics, enhancing mitochondrial function could augment cardiac function. Using a supplement such as D-ribose could improve mitochondrial function by increasing ATP and enhancing cardiac performance for patients with HFpEF. There is a recently completed clinical trial with HFpEF patients that indicates D-ribose increases ATP production and improves cardiac ejection fraction.

Role of mitochondrial dysfunction and PINK1/Parkin-mediated mitophagy in Cd-induced hepatic lipid accumulation in chicken embryos

The present study was performed to investigate the effects of Cd exposure on lipid metabolism and mitochondrial dysfunction and to explore the role of mitophagy in Cd-induced dysregulation of lipid metabolism in chicken embryo liver tissues and hepatocytes. To this end, seven-day-old chicken embryos were exposed to different concentrations of Cd for 7 days, and primary chicken embryo hepatocytes were treated with Cd at four different concentrations for 6 h. Furthermore, the mitophagy inhibitor cyclosporine A (CsA) was used to investigate the role of mitophagy in Cd-induced disruption of lipid metabolism. Lipid accumulation, the expression levels of genes involved in lipid metabolism, mitochondrial dysfunction, and mitophagy were measured. The results demonstrated that Cd exposure increases hepatic triglyceride (TG) accumulation and the expression levels of lipogenic genes while decreasing those of lipolytic genes. Furthermore, Cd exposure was observed to alter mitochondrial morphology in terms of reduced size, excessive mitochondrial damage, and the formation of mitophagosomes. The co-localization of lysosome-associated membrane glycoprotein 2 and LC3 puncta was significantly increased in primary chicken embryo hepatocytes after Cd exposure. Moreover, Cd exposure increased LC3, PINK1, and Parkin protein expression levels. CsA effectively alleviated Cd-induced mitochondrial dysfunction, blocked mitochondrial membrane potential collapse, and suppressed PINK1/Parkin-mediated mitophagy. Furthermore, CsA treatment reversed the Cd-induced TG accumulation in liver tissues but further increased it in hepatocytes. Taken together, our findings demonstrate (for the first time) the importance of mitochondrial dysfunction and mitophagy via the PINK1/Parkin pathway in Cd-induced disruption of lipid metabolism.

The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery.

Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.

Whole‑genome identification and systematic analysis of lncRNA‑mRNA co‑expression profiles in patients with cutaneous basal cell carcinoma.

Cutaneous basal cell carcinoma (BCC) is a common subtype of malignant skin tumor with low invasiveness. Early diagnosis and treatment of BCC and the identification of specific biomarkers are particularly urgent. Long non-coding RNAs (lncRNAs) have been shown to be associated with the development of various tumors, including BCC. The present study conducted a comparative analysis of the differential expression of lncRNAs and mRNAs through whole-genome technology. Microarray analyses were used to identify differentially expressed (DE) lncRNAs and DE mRNAs. Reverse transcription-quantitative (RT-q) PCR confirmed the differential expression of 10 lncRNAs in BCC. Subsequently, a lncRNA-mRNA co-expression network was constructed using the top 10 DE lncRNAs. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the possible biological effects of the identified mRNAs and to speculate on the possible biological effects of the lncRNAs. A total of 1,838 DE lncRNAs and 2,010 DE mRNAs were identified and 10 of the DE lncRNAs were confirmed by RT-qPCR. A lncRNA-mRNA co-expression network comprising 166 specific co-expressed lncRNAs and mRNAs was constructed using the top 10 DE lncRNAs. According to the results of the GO and KEGG analyses, lncRNA XR_428612.1 may serve an important role in mitochondrial dysfunction and the progression of BCC by modulating TICAM1, USMG5, COX7A2, FBXO10, ATP5E and TIMM8B. The present study provided whole-genome identification and a systematic analysis of lncRNA-mRNA co-expression profiles in BCC.

The role of mitochondria in metabolic disease: a special emphasis on heart dysfunction.

Metabolic diseases (MetDs) embrace a series of pathologies characterized by abnormal body glucose usage. The known diseases included in this group are metabolic syndrome, prediabetes and diabetes mellitus types 1 and 2. All of them are chronic pathologies that present metabolic disturbances and are classified as multi-organ diseases. Cardiomyopathy has been extensively described in diabetic patients without overt macrovascular complications. The heart is severely damaged during the progression of the disease; in fact, diabetic cardiomyopathies are the main cause of death in MetDs. Insulin resistance, hyperglycaemia and increased free fatty acid metabolism promote cardiac damage through mitochondria. These organelles supply most of the energy that the heart needs to beat and to control essential cellular functions, including Ca2+ signalling modulation, reactive oxygen species production and apoptotic cell death regulation. Several aspects of common mitochondrial functions have been described as being altered in diabetic cardiomyopathies, including impaired energy metabolism, compromised mitochondrial dynamics, deficiencies in Ca2+ handling, increases in reactive oxygen species production, and a higher probability of mitochondrial permeability transition pore opening. Therefore, the mitochondrial role in MetD-mediated heart dysfunction has been studied extensively to identify potential therapeutic targets for improving cardiac performance. Herein we review the cardiac pathology in metabolic syndrome, prediabetes and diabetes mellitus, focusing on the role of mitochondrial dysfunctions.

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes.

Mitochondrial dysfunction is known to be associated with a wide range of human pathologies, such as cancer, metabolic, and cardiovascular diseases. One of the possible ways of mitochondrial involvement in the cellular damage is excessive production of reactive oxygen and nitrogen species (ROS and RNS) that cannot be effectively neutralized by existing antioxidant systems. In mitochondria, ROS and RNS can contribute to protein and mitochondrial DNA (mtDNA) damage causing failure of enzymatic chains and mutations that can impair mitochondrial function. These processes further lead to abnormal cell signaling, premature cell senescence, initiation of inflammation, and apoptosis. Recent studies have identified numerous mtDNA mutations associated with different human pathologies. Some of them result in imbalanced oxidative phosphorylation, while others affect mitochondrial protein synthesis. In this review, we discuss the role of mtDNA mutations in cancer, diabetes, cardiovascular diseases, and atherosclerosis. We provide a list of currently described mtDNA mutations associated with each pathology and discuss the possible future perspective of the research.

Melatonin prevents blood-retinal barrier breakdown and mitochondrial dysfunction in high glucose and hypoxia-induced in vitro diabetic macular edema model

Diabetic macular edema (DME) is a leading cause of blindness in diabetic retinopathy. Prolonged hyperglycemia plus hypoxia contributes to DME pathogenesis. Retinal pigmented epithelial cells comprise the outer blood-retinal barrier and are essential for maintaining physiological functioning of the retina. Melatonin acts as an antioxidant and regulator of mitochondrial bioenergetics and has a protective effect against ocular diseases. However, the role of mitochondrial dysfunction and the therapeutic potential of melatonin in DME remain largely unexplored. Here, we used an in vitro model of DME to investigate blood-retinal barrier integrity and permeability, angiogenesis, mitochondrial dynamics, and apoptosis signaling to evaluate the potential protective efficacy of melatonin in DME. We found that melatonin prevents cell hyper-permeability and outer barrier breakdown by reducing HIF-1α, HIF-1β and VEGF and VEGF receptor gene expression. In addition, melatonin reduced the expression of genes involved in mitochondrial fission (DRP1, hFis1, MIEF2, MFF), mitophagy (PINK, BNip3, NIX), and increased the expression of genes involved in mitochondrial biogenesis (PGC-1α, NRF2, PPAR-γ) to maintain mitochondrial homeostasis. Moreover, melatonin prevented apoptosis of retinal pigmented epithelial cells. Our results suggest that mitochondrial dysfunction may be involved in DME pathology, and melatonin may have therapeutic value in DME, by targeting signaling in mitochondria.

The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.

High Dietary Fat Consumption Impairs Axonal Mitochondrial Function In Vivo.

Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia in vitro demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis in vivo We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca2+ levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca2+ levels and impairs impulse conduction within the saphenous nerve in prediabetic PN.SIGNIFICANCE STATEMENT Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system in vivo is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia in vivo.

Organic dust exposure induces stress response and mitochondrial dysfunction in monocytic cells.

Exposure to airborne organic dust (OD), rich in microbial pathogen-associated molecular patterns (PAMPs), is shown to induce lung inflammation. A common manifestation in lung inflammation is altered mitochondrial structure and bioenergetics that regulate mitochondrial ROS (mROS) and feed a vicious cycle of mitochondrial dysfunction. The role of mitochondrial dysfunction in other airway diseases is well known. However, whether OD exposure induces mitochondrial dysfunction remains elusive. Therefore, we tested a hypothesis that organic dust extract (ODE) exposure induces mitochondrial stress using a human monocytic cell line (THP1). We examined whether co-exposure to ethyl pyruvate (EP) or mitoapocynin (MA) could rescue ODE exposure induced mitochondrial changes. Transmission electron micrographs showed significant differences in cellular and organelle morphology upon ODE exposure. ODE exposure with and without EP co-treatment increased the mtDNA leakage into the cytosol. Next, ODE exposure increased PINK1, Parkin, cytoplasmic cytochrome c levels, and reduced mitochondrial mass and cell viability, indicating mitophagy. MA treatment was partially protective by decreasing Parkin expression, mtDNA and cytochrome c release and increasing cell viability.

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

Mitochondrial dysfunction has been suggested to be a risk factor for sensorineural hearing loss (SNHL) induced by aging, noise, ototoxic drugs, and gene. Reactive oxygen species (ROS) are mainly derived from mitochondria, and oxidative stress induced by ROS contributes to cochlear damage as well as mitochondrial DNA mutations, which may enhance the sensitivity and severity of hearing loss and disrupt ion homeostasis (e.g., Ca2+ homeostasis). The formation and accumulation of ROS further undermine mitochondrial components and ultimately lead to apoptosis and necrosis. SIRT3–5, located in mitochondria, belong to the family of sirtuins, which are highly conserved deacetylases dependent on nicotinamide adenine dinucleotide (NAD+). These deacetylases regulate diverse cellular biochemical activities. Recent studies have revealed that mitochondrial sirtuins, especially SIRT3, modulate ROS levels in hearing loss pathologies. Although the precise functions of SIRT4 and SIRT5 in the cochlea remain unclear, the molecular mechanisms in other tissues indicate a potential protective effect against hearing loss. In this review, we summarize the current knowledge regarding the role of mitochondrial dysfunction in hearing loss, discuss possible functional links between mitochondrial sirtuins and SNHL, and propose a perspective that SIRT3–5 have a positive effect on SNHL.

Proteomic Profiling of Lysine Acetylation Indicates Mitochondrial Dysfunction in the Hippocampus of Gut Microbiota-Absent Mice.

Major depressive disorder (MDD) is a leading cause of disability around the world and contributes greatly to the global burden of disease. Mounting evidence suggests that gut microbiota dysbiosis may be involved in the pathophysiology of MDD through the microbiota–gut–brain axis. Recent research suggests that epigenetic modifications might relate to depression. However, our knowledge of the role of epigenetics in host–microbe interactions remains limited. In the present study, we used a combination of affinity enrichment and high-resolution liquid chromatography tandem mass spectrometry analysis to identify hippocampal acetylated proteins in germ-free and specific pathogen-free mice. In total, 986 lysine acetylation sites in 543 proteins were identified, of which 747 sites in 427 proteins were quantified. Motif analysis identified several conserved sequences surrounding the acetylation sites, including D∗Kac, DKac, KacY, KacD, and D∗∗Kac. Gene ontology annotations revealed that these differentially expressed acetylated proteins were involved in multiple biological functions and were mainly located in mitochondria. In addition, pathway enrichment analysis demonstrated that oxidative phosphorylation and the tricarboxylic acid cycle II (eukaryotic), both of which are exclusively localized to the mitochondria, were the primarily disturbed functions. Taken together, this study indicates that lysine acetylation alterations may play a pivotal role in mitochondrial dysfunction and may be a mechanism by which gut microbiota regulate brain function and behavioral phenotypes.

Sepsis-induced myocardial dysfunction: the role of mitochondrial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is a condition manifested by an intrinsic myocardial systolic and diastolic dysfunction during sepsis, which is associated with worse clinical outcomes and a higher mortality. Several pathophysiological mechanisms including mitochondrial dysfunction, abnormal body immune reaction, metabolic reprogramming, excessive production of reactive oxygen species (ROS), and disorder of calcium regulation have been involved in SIMD. Mitophagy has potential role in protecting myocardial cells in sepsis, especially in survivors. In the current review, we focus on the role of mitochondrial dysfunction and other mitochondria-related mechanisms including immunologicimbalance, energetic reprogramming, mitophagy, and pyroptosis in the mechanisms of SIMD.