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Nature Immunology Mar 2024The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity....
The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8 T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8 T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
Topics: Humans; CD8-Positive T-Lymphocytes; Lactic Acid; Lithium Carbonate; Mitochondria; Neoplasms; Antimanic Agents
PubMed: 38263463
DOI: 10.1038/s41590-023-01738-0 -
Cells Oct 2023Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except... (Review)
Review
Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform 'oxidative phosphorylation (OX PHOS)', which are expressed by the mitochondria's self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials.
Topics: Child; Humans; Mitochondrial Diseases; Mitochondria; DNA, Mitochondrial; Oxidative Phosphorylation; Mutation
PubMed: 37887337
DOI: 10.3390/cells12202494 -
Blood Jul 2023
Topics: Humans; Oxidative Phosphorylation; Mitochondria; Cell Line, Tumor; Leukemia, Myeloid, Acute
PubMed: 37498585
DOI: 10.1182/blood.2023021129 -
Nature Cell Biology Nov 2023Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies...
Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.
Topics: Animals; Male; Semen; Sperm Motility; Spermatozoa; Fertility; Caenorhabditis elegans; Mitochondria
PubMed: 37945830
DOI: 10.1038/s41556-023-01264-z -
Scientific Reports Apr 2024Mitochondria, the powerhouse and the vital signaling hub of the cell, participate in a variety of biological processes, such as apoptosis, redox responses, cell...
Mitochondria, the powerhouse and the vital signaling hub of the cell, participate in a variety of biological processes, such as apoptosis, redox responses, cell senescence, autophagy, and iron homeostasis. Mitochondria form a mostly tubular network, made up of an outer and a cristeae-forming inner membrane. The network undergoes dynamic fusion and fission that change its morphological structure according to the functional needs. Approximately 1500 mitochondrial proteins encoded by nuclear genome plus over 10 proteins encoded by mitochondrial DNA are folded and assembled in the mitochondria under a high-fidelity control system. These proteins are involved in oxidative phosphorylation, metabolism, network and cristae dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance. This Collection gathers original research that advances our understanding of the monitoring techniques and pathophysiological significance of mitochondrial dynamics in health and disease.
Topics: Mitochondrial Dynamics; Humans; Mitochondria; Animals
PubMed: 38688939
DOI: 10.1038/s41598-024-59998-1 -
Journal of Biochemistry Feb 2024The cytoplasm of eukaryotes is dynamically zoned by membrane-bound and membraneless organelles. Cytoplasmic zoning allows various biochemical reactions to take place at... (Review)
Review
The cytoplasm of eukaryotes is dynamically zoned by membrane-bound and membraneless organelles. Cytoplasmic zoning allows various biochemical reactions to take place at the right time and place. Mitochondrion is a membrane-bound organelle that provides a zone for intracellular energy production and metabolism of lipids and iron. A key feature of mitochondria is their high dynamics: mitochondria constantly undergo fusion and fission, and excess or damaged mitochondria are selectively eliminated by mitophagy. Therefore, mitochondria are appropriate model systems to understand dynamic cytoplasmic zoning by membrane organelles. In this review, we summarize the molecular mechanisms of mitochondrial fusion and fission as well as mitophagy unveiled through studies using yeast and mammalian models.
Topics: Animals; Mitochondria; Mitophagy; Saccharomyces cerevisiae; Mitochondrial Dynamics; Mammals
PubMed: 38016932
DOI: 10.1093/jb/mvad098 -
Annual Review of Microbiology Sep 2023Apicomplexan parasites constitute more than 6,000 species infecting a wide range of hosts. These include important pathogens such as those causing malaria and... (Review)
Review
Apicomplexan parasites constitute more than 6,000 species infecting a wide range of hosts. These include important pathogens such as those causing malaria and toxoplasmosis. Their evolutionary emergence coincided with the dawn of animals. Mitochondrial genomes of apicomplexan parasites have undergone dramatic reduction in their coding capacity, with genes for only three proteins and ribosomal RNA genes present in scrambled fragments originating from both strands. Different branches of the apicomplexans have undergone rearrangements of these genes, with having massive variations in gene arrangements spread over multiple copies. The vast evolutionary distance between the parasite and the host mitochondria has been exploited for the development of antiparasitic drugs, especially those used to treat malaria, wherein inhibition of the parasite mitochondrial respiratory chain is selectively targeted with little toxicity to the host mitochondria. We describe additional unique characteristics of the parasite mitochondria that are being investigated and provide greater insights into these deep-branching eukaryotic pathogens.
Topics: Animals; Mitochondria; Toxoplasma; Biological Evolution; Malaria
PubMed: 37406344
DOI: 10.1146/annurev-micro-032421-120540 -
Genes Sep 2023Mitochondrial dynamics, including fission and fusion processes, are essential for heart health. Mitochondria, the powerhouses of cells, maintain their integrity through... (Review)
Review
Mitochondrial dynamics, including fission and fusion processes, are essential for heart health. Mitochondria, the powerhouses of cells, maintain their integrity through continuous cycles of biogenesis, fission, fusion, and degradation. Mitochondria are relatively immobile in the adult heart, but their morphological changes due to mitochondrial morphology factors are critical for cellular functions such as energy production, organelle integrity, and stress response. Mitochondrial fusion proteins, particularly Mfn1/2 and Opa1, play multiple roles beyond their pro-fusion effects, such as endoplasmic reticulum tethering, mitophagy, cristae remodeling, and apoptosis regulation. On the other hand, the fission process, regulated by proteins such as Drp1, Fis1, Mff and MiD49/51, is essential to eliminate damaged mitochondria via mitophagy and to ensure proper cell division. In the cardiac system, dysregulation of mitochondrial dynamics has been shown to cause cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and various cardiac diseases, including metabolic and inherited cardiomyopathies. In addition, mitochondrial dysfunction associated with oxidative stress has been implicated in atherosclerosis, hypertension and pulmonary hypertension. Therefore, understanding and regulating mitochondrial dynamics is a promising therapeutic tool in cardiac diseases. This review summarizes the role of mitochondrial morphology in heart diseases for each mitochondrial morphology regulatory gene, and their potential as therapeutic targets to heart diseases.
Topics: Humans; Mitochondrial Dynamics; Heart Diseases; Heart Failure; Mitochondria; Apoptosis; Mitochondrial Proteins
PubMed: 37895224
DOI: 10.3390/genes14101876 -
Mitochondrion Sep 2023Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms of epilepsy makes diagnosis challenging.... (Review)
Review
Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms of epilepsy makes diagnosis challenging. Diagnosis and monitoring of childhood epilepsy add to the need for non-invasive biomarkers, especially when evaluating antiseizure medications. Although underlying mechanisms of epileptogenesis are not fully understood, evidence for mitochondrial involvement is substantial. Seizures affect 35%-60% of patients diagnosed with mitochondrial diseases. Mitochondrial dysfunction is pathophysiological in various epilepsies, including those of non-mitochondrial origin. Decreased ATP production caused by malfunctioning brain cell mitochondria leads to altered neuronal bioenergetics, metabolism and neurological complications, including seizures. Iron-dependent lipid peroxidation initiates ferroptosis, a cell death pathway that aligns with altered mitochondrial bioenergetics, metabolism and morphology found in neurodegenerative diseases (NDDs). Studies in mouse genetic models with seizure phenotypes where the function of an essential selenoprotein (GPX4) is targeted suggest roles for ferroptosis in epilepsy. GPX4 is pivotal in NDDs, where selenium protects interneurons from ferroptosis. Selenium is an essential central nervous system micronutrient and trace element. Low serum concentrations of selenium and other trace elements and minerals, including iron, are noted in diagnosing childhood epilepsy. Selenium supplements alleviate intractable seizures in children with reduced GPX activity. Copper and cuproptosis, like iron and ferroptosis, link to mitochondria and NDDs. Connecting these mechanistic pathways to selenoproteins provides new insights into treating seizures, pointing to using medicines including prodrugs of lipoic acid to treat epilepsy and to potential alternative therapeutic approaches including transcranial magnetic stimulation (transcranial), photobiomodulation and vagus nerve stimulation.
Topics: Animals; Mice; Selenium; Mitochondria; Epilepsy; Seizures; Iron
PubMed: 37582467
DOI: 10.1016/j.mito.2023.08.002 -
Nature Communications Oct 2023PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant...
PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7 mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
Topics: Animals; Mice; Mitochondrial Proteins; Mitophagy; Fibroblasts; Mitochondria; Phosphoric Monoester Hydrolases
PubMed: 37833277
DOI: 10.1038/s41467-023-42069-w