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Annual Review of Physiology Feb 2024Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron.... (Review)
Review
Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.
Topics: Humans; Kidney Tubules; Bartter Syndrome; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria
PubMed: 38012047
DOI: 10.1146/annurev-physiol-042222-025000 -
Neurotherapeutics : the Journal of the... Jan 2024Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting... (Review)
Review
Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.
Topics: Humans; Neurodegenerative Diseases; Mitochondria; Reactive Oxygen Species; Alzheimer Disease; Mitochondrial Diseases
PubMed: 38241161
DOI: 10.1016/j.neurot.2023.10.002 -
Nature Biotechnology Mar 2024A number of mitochondrial diseases in humans are caused by point mutations that could be corrected by base editors, but delivery of CRISPR guide RNAs into the...
A number of mitochondrial diseases in humans are caused by point mutations that could be corrected by base editors, but delivery of CRISPR guide RNAs into the mitochondria is difficult. In this study, we present mitochondrial DNA base editors (mitoBEs), which combine a transcription activator-like effector (TALE)-fused nickase and a deaminase for precise base editing in mitochondrial DNA. Combining mitochondria-localized, programmable TALE binding proteins with the nickase MutH or Nt.BspD6I(C) and either the single-stranded DNA-specific adenine deaminase TadA8e or the cytosine deaminase ABOBEC1 and UGI, we achieve A-to-G or C-to-T base editing with up to 77% efficiency and high specificity. We find that mitoBEs are DNA strand-selective mitochondrial base editors, with editing results more likely to be retained on the nonnicked DNA strand. Furthermore, we correct pathogenic mitochondrial DNA mutations in patient-derived cells by delivering mitoBEs encoded in circular RNAs. mitoBEs offer a precise, efficient DNA editing tool with broad applicability for therapy in mitochondrial genetic diseases.
Topics: Humans; Gene Editing; DNA, Mitochondrial; CRISPR-Cas Systems; RNA, Guide, CRISPR-Cas Systems; Mitochondria; Mitochondrial Diseases; Deoxyribonuclease I; Cytosine
PubMed: 37217751
DOI: 10.1038/s41587-023-01791-y -
Genes & Diseases May 2024Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal.... (Review)
Review
Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal. Mitochondrial diseases are often caused by mitochondrial DNA mutations. Currently, there is no curative treatment for patients with pathogenic mitochondrial DNA mutations. With the rapid development of traditional gene editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases methods, there has been a search for a mitochondrial gene editing technology that can edit mutated mitochondrial DNA; however, there are still some problems hindering the application of these methods. The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing. In this paper, we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.
PubMed: 38292200
DOI: 10.1016/j.gendis.2023.06.026 -
Frontiers in Cell and Developmental... 2023The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases,... (Review)
Review
The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.
PubMed: 37731815
DOI: 10.3389/fcell.2023.1257651 -
Circulation Research Mar 2024Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains...
BACKGROUND
Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined.
METHODS
Using human induced pluripotent stem cells-derived cardiomyocytes and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity.
RESULTS
Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor 2α) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector-ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibitor protected human induced pluripotent stem cell-derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro.
CONCLUSIONS
Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.
Topics: Humans; Animals; Mice; Protein Serine-Threonine Kinases; Cardiotoxicity; Proteomics; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Protein Kinase Inhibitors; Mitochondrial Diseases; Adenosine Triphosphate; Imidazoles; Pyridazines
PubMed: 38323474
DOI: 10.1161/CIRCRESAHA.123.323683 -
Biochimica Et Biophysica Acta.... Oct 2023Mitochondrial diseases are a group of clinical disorders caused by mutations in the genes encoded by either the nuclear or the mitochondrial genome involved in... (Review)
Review
Mitochondrial diseases are a group of clinical disorders caused by mutations in the genes encoded by either the nuclear or the mitochondrial genome involved in mitochondrial oxidative phosphorylation. Disorders become evident when mitochondrial dysfunction reaches a cell-specific threshold. Similarly, the severity of disorders is related to the degree of gene mutation. Clinical treatments for mitochondrial diseases mainly rely on symptomatic management. Theoretically, replacing or repairing dysfunctional mitochondria to acquire and preserve normal physiological functions should be effective. Significant advances have been made in gene therapies, including mitochondrial replacement therapy, mitochondrial genome manipulation, nuclease programming, mitochondrial DNA editing, and mitochondrial RNA interference. In this paper, we review the recent progress in these technologies by focusing on advancements that overcome limitations.
Topics: Humans; Genome, Mitochondrial; DNA, Mitochondrial; Mitochondrial Diseases; Mitochondria; Mutation
PubMed: 37429560
DOI: 10.1016/j.bbadis.2023.166804 -
Redox Biology Feb 2024Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it...
Ketone bodies are considered as an alternative energy source for diabetic cardiomyopathy (DCM) and can improve the energy supply of the heart muscle, suggesting that it may be an important area of research and development as a therapeutic target for DCM. Cumulative cardiovascular trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in diabetic populations. Whether SGLT2 inhibitors improve DCM by enhancing ketone body metabolism remains and whether they help prevent oxidative damage remains to be clarified. Here, we present the combined results of nine GSE datasets for diabetic cardiomyopathy (GSE215979, GSE161931, GSE145294, GSE161052, GSE173384, GSE123975, GSE161827, GSE210612, and GSE5606). We found significant up-regulated gene 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) and down-regulated gene 3-hydroxybutyrate dehydrogenase (BDH1) and 3-oxoacid CoA-transferase1 (OXCT1), respectively. Based on the analysis of the constructed protein interaction network, it was found that HMGCS2 was in the core position of the interaction network. In addition, Gene ontology (GO) enrichment analysis mainly focused on redox process, acyl-CoA metabolic process, catalytic activity, redox enzyme activity and mitochondria. The activity of HMGCS2 in DCM heart was increased, while the expression of ketolysis enzymes BDH1 and OXCT1 was inhibited. In vivo, Empagliflozin (Emp) treated DCM group significantly decreased ventricular weight, myocardial cell cross-sectional area, and myocardial fibrosis. In addition, Emp further promoted the activity of BDH1 and OXCT1, increased the utilization of ketone bodies, further promoted the activity of HMGCS2 in DCM, and increased the synthesis of ketone bodies, prevented mitochondrial breakage and dysfunction, increased myocardial ATP to provide sufficient energy, inhibited oxidative stress and apoptosis of cardiac cells ex vivo, and improved the myocardial dysfunction of DCM. Emp can improve mitochondrial dysfunction in diabetic cardiomyopathy by regulating ketone body metabolism and oxidative stress. These findings provide a theoretical basis for evaluating Emp as a treatment for DCM.
Topics: Humans; Diabetic Cardiomyopathies; Oxidative Stress; Myocytes, Cardiac; Ketone Bodies; Mitochondrial Diseases; Diabetes Mellitus; Benzhydryl Compounds; Glucosides
PubMed: 38160540
DOI: 10.1016/j.redox.2023.103010 -
Current Opinion in Endocrinology,... Feb 2024Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have... (Review)
Review
PURPOSE OF REVIEW
Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have clinical features that are distinct from the more common forms. We provide an overview of mitochondrial disorder genetics and phenotypes, focusing on recent studies regarding identification and treatment of associated endocrinopathies.
RECENT FINDINGS
Known endocrine phenotypes of mitochondrial disorders continue to expand, and now include growth hormone deficiency, hypogonadism, precocious puberty, hypoparathyroidism, hypo- and hyperthyroidism, diabetes, and adrenal insufficiency. Recent studies suggest several genotype-phenotype correlations, including those related to nuclear variants. Diagnosis is important, as special considerations should be made in the management of endocrinopathies in mitochondrial patients. Finally, new mitochondrial replacement strategies may soon be available for women interested in preventing mitochondrial disease transmission to offspring.
SUMMARY
Patients with multiple endocrinopathies or atypical endocrinopathies should be evaluated for primary mitochondrial disease, as a diagnosis may impact management of these individuals.
Topics: Humans; Female; Endocrine System Diseases; Diabetes Mellitus; Puberty, Precocious; Mitochondrial Diseases; Hyperthyroidism; Adrenal Insufficiency
PubMed: 38047549
DOI: 10.1097/MED.0000000000000848 -
Cells Aug 2023Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial... (Review)
Review
Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.
Topics: Young Adult; Humans; Male; Female; Optic Atrophy, Hereditary, Leber; Antioxidants; Sexism; DNA, Mitochondrial; Genetic Therapy
PubMed: 37566092
DOI: 10.3390/cells12152013