Mitochondria at the crossroads of health and disease

Cell, Год журнала: 2024, Номер 187(11), С. 2601 - 2627

Опубликована: Май 1, 2024

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence life. How their structure function are dynamically tuned in response to tissue-specific needs for energy, growth repair, renewal is being increasingly understood. respond intrinsic extrinsic stresses can alter cell organismal by inducing metabolic signaling within cells distal tissues. Here, we review how centrality mitochondrial functions manifests health a broad spectrum diseases aging.

Язык: Английский

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High-resolution in situ structures of mammalian respiratory supercomplexes

Nature, Год журнала: 2024, Номер 631(8019), С. 232 - 239

Опубликована: Май 29, 2024

Mitochondria play a pivotal part in ATP energy production through oxidative phosphorylation, which occurs within the inner membrane series of respiratory complexes

Язык: Английский

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Mitochondrial membrane lipids in the regulation of bioenergetic flux

Cell Metabolism, Год журнала: 2024, Номер 36(9), С. 1963 - 1978

Опубликована: Авг. 23, 2024

SummaryOxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by biosynthetic machinery localized in IMM class-specific transporters that limit traffic out of mitochondria. This unique composition appears to be essential for functions mitochondria, particularly OXPHOS, its effects on direct lipid-to-protein interactions, properties, cristae ultrastructure. review highlights biological significance lipids, with particular spotlight role lipids bioenergetics. We describe pathways biosynthesis provide evidence their roles physiology, implications human disease, mechanisms which they regulate

Язык: Английский

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Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease

Physiology, Год журнала: 2024, Номер 39(5), С. 247 - 268

Опубликована: Май 7, 2024

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the uniporter rapidly enhances NADH ATP production. However, maintaining homeostasis critical: insufficient impairs stress adaptation, overload can trigger cell death. this review, we delve into recent insights further defining relationship between dynamics oxidative phosphorylation. Our focus on how such regulation affects cardiac function disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, cardiomyopathies, Barth syndrome, Friedreich's ataxia. Several themes emerge from data. First, critical for fuel substrate selection, metabolite import, matching of supply to demand. Second, regulates both production response reactive oxygen species (ROS), balance its pro- antioxidant effects key it contributes pathological states. Third, exerts localized electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These hinge specific transporters, as or Na+/Ca2+ exchanger, may be noticeable acutely, contributing differently phenotypes depending whether transporters are acutely chronically modified. Perturbations these novel relationships during disease states either serve compensatory exacerbate impairments Consequently, targeting holds promise a therapeutic strategy variety diseases characterized contractile failure arrhythmias.

Язык: Английский

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Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity

Nature Metabolism, Год журнала: 2024, Номер 6(6), С. 1024 - 1035

Опубликована: Апрель 30, 2024

Abstract The oxidative phosphorylation system 1 in mammalian mitochondria plays a key role transducing energy from ingested nutrients 2 . Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial intricately linked metabolic diseases promotes tumour growth 3–5 Here, we demonstrate that oral treatment with an inhibitor transcription (IMT) 6 shifts whole-animal towards fatty acid oxidation, which, turn, leads rapid normalization body weight, reversal hepatosteatosis restoration normal glucose tolerance male mice high-fat diet. Paradoxically, the IMT causes severe reduction capacity concomitant marked upregulation oxidation liver, as determined by proteomics metabolomics analyses. complex I, main dehydrogenase feeding electrons into ubiquinone (Q) pool, whereas levels electron transfer flavoprotein other dehydrogenases connected Q pool are increased. This rewiring caused reduced mtDNA expression liver provides principle for drug obesity obesity-related pathology.

Язык: Английский

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Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 27, 2025

Sequence evolution of protein complexes (PCs) is constrained by protein-protein interactions (PPIs). PPI-interfaces are predominantly conserved and hotspots for disease-related mutations. How do lipid-protein (LPIs) constrain sequence membrane-PCs? We explore Respiratory Complexes (RCs) as a case study these allow to compare in subunits exposed both lipids inner-mitochondrial membrane (IMM) lipid-free aqueous matrix. find that lipid-exposed surfaces the IMM-subunits but not matrix populated with non-PPI disease-causing mutations signifying LPIs stabilizing RCs. Further, including their show high intra-kingdom conservation remarkably diverge beyond. Molecular Dynamics simulation suggests contrasting structurally superimposable sequence-wise diverged IMM-exposed helices Complex I (CI) subunit Ndufa1 from human Arabidopsis depending on kingdom-specific unsaturation cardiolipin fatty acyl chains. cellulo assays consolidate inter-kingdom incompatibility Ndufa1-helices due amino acids. Plant-specific unsaturated acids cells also trigger CI-instability. Taken together, we posit altered calibrate at IMM-arms eukaryotic Here authors lipid sequences membrane-embedded experience selection pressure unsaturation. This highlights role evolution, possible roles mitochondrial diseases.

Язык: Английский

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In-cell architecture of the mitochondrial respiratory chain

Science, Год журнала: 2025, Номер 387(6740), С. 1296 - 1301

Опубликована: Март 20, 2025

Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these native cells debated. We used situ cryo–electron tomography visualize structures several major mitochondrial Chlamydomonas reinhardtii cells. ATP synthases segregate into curved flat crista membrane domains, respectively. Respiratory I, III, IV assemble a respirasome supercomplex, from which we determined 5-angstrom (Å) resolution structure showing binding electron carrier cytochrome c . Combined with single-particle microscopy at 2.4-Å resolution, model how organize inside mitochondria.

Язык: Английский

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The functional significance of mitochondrial respiratory chain supercomplexes

EMBO Reports, Год журнала: 2023, Номер 24(11)

Опубликована: Окт. 12, 2023

The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four complexes cooperate the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over inner membrane that powers ATP synthesis. This electron transport relies on mobile carries functionally connect complexes. While individual can operate independently, they are situ organized into large assemblies termed supercomplexes. Recent structural and functional studies have provided some answers question whether supercomplex organization confers advantage for cellular conversion. However, jury still out, regarding universality these claims. In this review, we discuss current knowledge significance MRC supercomplexes, highlight experimental limitations, suggest potential new strategies overcome obstacles.

Язык: Английский

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Synchronized assembly of the oxidative phosphorylation system controls mitochondrial respiration in yeast

Developmental Cell, Год журнала: 2024, Номер 59(8), С. 1043 - 1057.e8

Опубликована: Март 19, 2024

Control of protein stoichiometry is essential for cell function. Mitochondrial oxidative phosphorylation (OXPHOS) presents a complex stoichiometric challenge as the ratio electron transport chain (ETC) and ATP synthase must be tightly controlled, assembly requires coordinated integration proteins encoded in nuclear mitochondrial genome. How correct OXPHOS achieved unknown. We identify Regulatory hub respiratory Assembly (MiRA) platform, which synchronizes ETC biogenesis yeast. Molecularly, this by stop-and-go mechanism: uncharacterized Mra1 stalls IV assembly. Two "Go" signals are required progression: binding factor Rcf2 interaction with an Atp9-translating mitoribosome induce degradation, allowing synchronized maturation synthase. Failure mechanism results death. MiRA controls assembly, ensuring machineries two different genomes.

Язык: Английский

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Status of Mitochondrial Oxidative Phosphorylation during the Development of Heart Failure

Antioxidants, Год журнала: 2023, Номер 12(11), С. 1941 - 1941

Опубликована: Окт. 31, 2023

Mitochondria are specialized organelles, which serve as the “Power House” to generate energy for maintaining heart function. These organelles contain various enzymes oxidation of different substrates well electron transport chain in form Complexes I V producing ATP through process oxidative phosphorylation (OXPHOS). Several studies have shown depressed OXPHOS activity due defects one or more components substrate and systems leads depletion myocardial high-energy phosphates (both creatine phosphate ATP). Such changes mitochondria appear be development stress, inflammation, Ca2+-handling abnormalities failing heart. Although some investigations failed detect any heart, such results a loss Ca2+ during mitochondrial isolation procedure. There is ample evidence suggest that Ca2+-overload occurs, associated with impaired The depression may also increased level reactive oxygen species, formed consequence complexes Various metabolic interventions promote generation been reported beneficial therapy failure. Accordingly, it suggested plays an important role

Язык: Английский

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