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Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease patients as well as several animal models of AD and Parkinson's disease. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show

Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy.

Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2α CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivatio

Trafficking of protein kinases to mitochondria: Implications for ischemic stroke.

Stroke is a major cause of death and permanent disability, which is described by abrupt loss of neuronal energy, oxidative injury, inflammat … ate to mitochondria under physiological and pathological conditions. Once localized, they influence mitochondrial dynamics, bioenergetics, reactive oxygen species (ROS) production, and programmed cell death. Dysregulation of these functions has been implicated in impaired mitophagy, aberrant calcium signaling, and processes associated with the pathogenesis of various ne …

Overexpression of c-Myc triggers p62 aggregation-mediated mitochondrial mitophagy in cabozantinib resistance of hepatocellular carcinoma.

Resistance to tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of hepatocellular carcinoma (HCC). Although dysregulation of mitochondrial dynamics has been implicated in the aggressive behaviors of various tumors, the specific role and underlying mechanisms by which this dysregulation contributes to cabozantinib resistance in HCC cells remains insufficiently characterized. By investigating mitochondrial dynamics as central regulators of cabozantinib resistance, this work specifically aims to discover actionable targets for restoring drug sensitivity in treatment…

Imbalance of mitochondrial fusion in peripheral blood mononuclear cells is associated with liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis.

Mitochondrial dysfunction and inflammation contribute to the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). This study aims to evaluate the potential association between mitochondrial dynamics and cell death markers from peripheral blood mononuclear cells (PBMCs) and the presence of MASH with significant liver fibrosis among metabolic dysfunction-associated steatotic liver disease (MASLD) patients. Consecutive patients undergoing bariatric surgery from January to December 2022 were included. Patients with histologic steatosis were classified into MASH with signific…

Effects of metformin on glucose metabolism and mitochondrial function in patients with obstructive sleep apnea: A pilot randomized trial.

Obstructive sleep apnea (OSA) is associated with increased risk for diabetes, and standard treatment with positive airway pressure (PAP) dev … y was obtained to evaluate mitochondrial respiratory capacity and expression of proteins related to mitochondrial dynamics and energy metabolism. Whole body insulin-sensitivity (Matsuda index) did not change in metformin or placebo treated groups. However, metformin treatment prevented increases in insulin release relative to placebo during follow-up. Insulin area under …

The immunoproteasome subunit β2i ameliorates myocardial ischemia/reperfusion injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Mitochondrial dynamics are critical for maintaining mitochondrial morphology and function during cardiac ischemia and reperfusion (I/R). The immunoproteasome complex is an inducible isoform of the proteasome that plays a key role in modulating inflammation and some cardiovascular diseases, but the importance of immunoproteasome catalytic subunit β2i (also known as LMP10 or MECL1) in regulating mitochondrial dynamics and cardiac I/R injury is largely unknown. Here, using β2i-knockout (KO) mice and rAAV9-β2i-injected mice, we discovered that β2i expression and its trypsin-like activity were sign…

High-fat diet feeding induces a depot-dependent response on the pro-inflammatory state and mitochondrial function of gonadal white adipose tissue.

Obesity has been related to a chronic pro-inflammatory state affecting white adipose tissue (WAT), which has a great impact on carbohydrate, … h more pronounced pro-inflammatory, hypoxic and insulin-resistant profile accompanied by changes in mitochondrial dynamics, probably associated with HFD-induced mitochondrial dysfunction. Thus, this explains the worse serum insulin sensitivity profile of male rats.

Mitochondrial maintenance as a novel target for treating steroid-induced osteonecrosis of femoral head: a narrative review.

The pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) remains unclear; however, emerging evidence suggests that mitochondrial injury plays a significant role. This review aims to elucidate the involvement of mitochondrial dysfunction in SONFH and explore potential therapeutic targets. A comprehensive literature search was conducted in PubMed, Web of Science, and Elsevier ScienceDirect, focusing on mitochondrial homeostasis, including mitophagy, mitochondrial biogenesis, mitochondrial dynamics, and oxidative stress in SONFH. Ultimately, we included and analyzed a total o…

Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.

Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions. This study employs a multi-omics approach to investigate the biochemical impact of AFG…

Достижения в исследованиях митохондриальной дисфункции в нейродегенеративных заболеваниях.

Учитывая высокий энергетический спрос нервной системы, митохондриальная дисфункция является ключевым фактором патогенез нейродегенеративных заболеваний. Таким образом, важное значение имеет всеобъемлющее понимание его механизмов и потенциальных целей в области лечения. В настоящем обзоре обсуждаются роли митохондриального окислительного стресса, изменения митохондриальной динамики и повреждения MtDNA при болезни Альцгеймера (AD), болезни Паркинсона (PD), болезни Хантингтона (HD) и множественном склерозе (MS). Кроме того, в нем резюмируется вклад новых технологических подходов в выявление митох

Совпадение в аннотации оригинала
Given the high energy demand of the nervous system, mitochondrial dysfunction is a key factor in the pathogenesis of neurodegenerative diseases. Thus, a comprehensive understanding of its mechanisms and potential therapeutic targets is essential. This review discusses the roles of mitochondrial oxidative stress, mitochondrial dynamics alterations, and mtDNA …

Redox-Mediated Mitochondrial Dysfunction as a Common Pathogenic Axis in Acute Kidney Injury and Chronic Kidney Disease.

Acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic kidney disease (DKD) are interconnected disorders linked by shared mechanisms involving redox imbalance and mitochondrial dysfunction. This review summarizes current evidence on the role of excessive reactive oxygen species (ROS) production, impaired oxidized nicotinamide adenine dinucleotide (NAD+) metabolism, altered mitochondrial bioenergetics, disrupted mitochondrial dynamics, and defective mitochondrial quality control pathways, including mitophagy and the mitochondrial unfolded protein response (UPRmt), in kidney disea…

Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy.

Mitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increa…

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification.

Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and any damage to SSCs may result in spermatogenic disorder and male infertility. Chromium (Cr) (VI) is a proven toxin, mutagen, and carcinogen, perpetually detrimental to environmental organisms due to its intricate and enduring detoxification process in vivo. Despite this, the deleterious effects of Cr (VI) on SSCs and the underlying mechanisms remain poorly understood. In this study, we identified that Cr (VI) impaired male reproductive system in mouse testes and induced mitochondrial dynamic imbalance and mitophagy in SSCs/

Shaping the mitochondrial inner membrane in health and disease.

Mitochondria play central roles in cellular energetics, metabolism and signalling. Efficient respiration, mitochondrial quality control, apoptosis and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodelling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. Inner membrane morphology is generated and maintained in particular by the mitochondrial contact site and cristae organizing system (MICOS), the F1 Fo -ATP synthase,

Novel insights into the role of mitochondria in diabetic cardiomyopathy: molecular mechanisms and potential treatments.

Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission a…

Single-cell atlas reveals multi-faced responses of losartan on tubular mitochondria in diabetic kidney disease.

BACKGROUND AND OBJECTIVE: Mitochondria are crucial to the function of renal tubular cells, and their dynamic perturbation in many aspects is … such as ROS production, apoptosis, membrane potential, adenosine triphosphate (ATP) synthesis, and mitochondrial dynamics, were involved in the protective mechanism of losartan on PT cells, thereby improving mitochondrial homeostasis. Consistent results were also obtained in mice and cellular experiments. In addition, we highlighted a specific renal tubular subpopulati …

Advances in Cardiolipin Analysis: Applications in Central Nervous System Disorders and Nutrition Interventions.

Cardiolipin (CL), a unique dimeric phospholipid predominantly enriched in the inner mitochondrial membrane, is a crucial determinant of mitochondrial structure and function. Its content, fatty acyl composition, and oxidation state are associated with mitochondrial bioenergetics, dynamics, and cellular signaling. Disruptions in CL metabolism are increasingly implicated in the pathogenesis of various central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and traumatic brain injury. This narrative review summarizes rece

Recent advances in mitochondrial fission and fusion in diabetic cardiomyopathy.

Diabetic cardiomyopathy (dCM) is characterized by myocardial dysfunction in diabetes and reflects interacting metabolic, redox, calcium, inf … will require human myocardial phenotyping, single-cell and spatial analyses, in vivo measurement of mitochondrial dynamics, cell-selective delivery, and standardized flux-based endpoints. The therapeutic goal should be restoration of adaptive mitochondrial dynamics rather than indiscriminate inhibition of fission or promotion of fusion.

NR4A1 Aggravates Myocardial Ischaemia-Reperfusion Injury by Inhibiting OPA1-Mediated Mitochondrial Fusion.

Mitochondrial fusion is an important process that protects the myocardium. However, mitochondrial fusion is often inhibited in myocardial is … ession with MYLS22 abrogates the effects of NR4A1 downregulation on IR. Furthermore, NR4A1 disrupts mitochondrial dynamics and activates the STING and NF-κB pathways. Insufficient mitochondrial fusion and increased apoptosis and inflammatory reactions worsen irreversible damage to cardiomyocytes. In conclusion, NR4A1 can exacerbate IR by inhibiting OPA1, causing mitocho …