Mitochondrial membrane synthesis, remodelling and cellular trafficking

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 48(1)

Published: June 14, 2024

Abstract Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders a group of approximately 400 monogenic arising from pathogenic genetic variants impacting structure, ultrastructure and/or function. Amongst these disorders, defects lipid biosynthesis, especially the unique membrane cardiolipin, biology an emerging characterised by clinical heterogeneity, but recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy 3‐methylglutaconic aciduria. This review discusses synthesis membrane, contact site cristae organising system (MICOS), dynamics trafficking, associated each processes. We highlight overlapping functions proteins involved biosynthesis protein import into mitochondria, pointing to overarching coordination synchronisation functions. also focuses on interactions between mitochondria other organelles, namely endoplasmic reticulum, peroxisomes, lysosomes droplets. signpost that may explain observation secondary dysfunction heterogeneous pathological Disruption organellar ultimately impairs homeostasis organismal health, highlighting central role human health disease.

Language: Английский

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Decanoylcarnitine improves liver mitochondrial dysfunction in hepatitis B virus infection by enhancing fatty acid β-oxidation

The Journal of Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Abstract Background The incidence of metabolic-associated steatotic liver disease in patients with chronic hepatitis B is increasing annually; however, the interaction between virus (HBV) infection and lipid metabolism remains unclear. This study attempted to clarify whether fatty acid regulation could alleviate mitochondrial dysfunction caused by HBV infection. Methods Public gene set human livers was analyzed, a proteomic analysis on mouse conducted explore metabolic disorders affected organelles associated effect decanoylcarnitine β-oxidation mitochondria investigated vivo vitro. pathways involved were shown confirmed Western blot. Results cause disorder CPT1A overexpression improve function hepatocytes. Furthermore, supplementation activate expression, thus improving repairing dysfunction. Proteomic suggests that stimulates peroxisome proliferator-activated receptor (PPAR) signaling pathway, PPARα most important among PPARs. Conclusions Impaired hepatocytes be partially restored exogenous decanoylcarnitine. It elucidated therapeutic potential provided new approach for diseases related

Language: Английский

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Characteristics of different lipid droplet-mitochondrial contacts patterns during lipid droplet metabolism in T2DM-induced MASLD

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 27, 2025

Mitochondrial function is crucial for hepatic lipid metabolism. Current research identifies two types of mitochondria based on their contact with droplets: peridroplet (PDM) and cytoplasmic (CM). This work aimed to investigate the alterations CM PDM in metabolic dysfunction-associated steatotic liver disease (MASLD) induced by spontaneous type-2 diabetes mellitus (T2DM) db/db mice. It was found that insulin resistance increased both number size droplets enhancing accumulation free fatty acids, which accompanied an increase contacts mitochondria. We described different patterns tight between small purified examining oxidation states morphological characteristics. In CM, enhanced acid resulted elongated surrounded single were responsible droplet consumption, while PDM, substrates synthesis promoted expansion assistance endoplasmic reticulum. These data show ways mitochondrial could provide new insights future

Language: Английский

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Tools to Dissect Lipid Droplet Regulation, Players, and Mechanisms

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Spurred by the authors' own recent discovery of reactive metabolite-regulated nexuses involving lipid droplets (LDs), this perspective discusses latest knowledge and multifaceted approaches toward deconstructing function these dynamic organelles, LD-associated localized signaling networks, protein players. Despite accumulating surrounding families pathways conserved importance for LD homeostasis surveillance maintenance across taxa, much remains to be understood at molecular level. In particular, metabolic stress-triggered contextual changes in LD-proteins' functions, crosstalk with other feedback loops how are specifically rewired disease states remain illuminated spatiotemporal precision. We hope promotes an increased interest essential organelles innovations new tools strategies better understand context-specific regulation critical organismal health.

Language: Английский

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Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis

Genome biology, Journal Year: 2025, Volume and Issue: 26(1)

Published: March 17, 2025

Dyslipidemia or hypercholesterolemia are among the main risk factors for cardiovascular diseases. Unraveling molecular basis of lipid cholesterol homeostasis would help to identify novel drug targets and develop effective therapeutics. Here, we adopt a systematic approach catalog genes underlying by combinatorial use high-throughput CRISPR screening, RNA sequencing, human genetic variant association analysis, proteomic metabolomic profiling. Such integrative multi-omics efforts gamma-glutamyltransferase GGT7 as an intriguing potential regulator. As SREBP2-dependent target, positively regulates cellular levels affects expression several metabolism genes. Furthermore, interacts with actin-dependent motor protein MYH10 control low-density lipoprotein (LDL-C) uptake into cells. Genetic ablation Ggt7 in mice leads reduced serum levels, supporting vivo role during homeostasis. Our study not only provides repertoire regulatory from multiple angles but also reveals causal link between metabolism.

Language: Английский

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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Language: Английский

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The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity

Antioxidants, Journal Year: 2024, Volume and Issue: 13(7), P. 820 - 820

Published: July 8, 2024

Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that NADPH-generating enzymes fuel lipogenesis in white adipose tissue (WAT) through the induction transcriptional regulators SREBP-1c and CHREBP. knockout mice, unlike controls, did not show an extended lifespan on DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) pentose phosphate pathway (PPP), while liver primarily synthesized folate cycle provided one-carbon units serine catabolism. During daily fasting diet, fatty acids are released from transported to peripheral tissues, where they used for beta-oxidation phospholipid lipid droplet synthesis, monounsaturated (MUFAs) may activate Nrf1 inhibit ferroptosis promote longevity. Decreased PPP stimulated browning protected high-fat high levels macrophages linked obesity. But oscillations [NADPH]/[NADP+] feeding cycles play important role maintaining metabolic plasticity drive Studies measuring malate/pyruvate as proxy [NADPH]/[NADP+], well studies using fluorescent biosensors expressed animal models monitor changes needed during ad libitum diets determine associated with

Language: Английский

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The Mitochondria Chronicles of Melatonin and ATP: Guardians of Phase Separation

Mitochondrial Communications, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Phase separation is a thermodynamic process used by all living organisms since the origin of life to rapidly assemble and disassemble membraneless condensates in response changes exogenous endogenous stress conditions. For ∼4.5 billion years, three major domains depended upon high chemical potential adenosine triphosphate (ATP) harness nonequilibrium reactions that govern formation suppression organelles via phase separation. Melatonin enhances unique chemistry ATP water, promoting solubilization moiety effect, supporting survival early an anoxic environment. Eukaryotes, including dinoflagellates plants, can produce melatonin extreme levels under as compensation for inadequate optimal regulation responses dependent The production mitochondria enables fine-tuning dynamics modulate proteins associated with production, biogenesis degradation, membrane dynamics, gene transcription, mitophagy, unfolded protein response, apoptosis/survival mitochondria. Exogenous application mitochondrial synergy, attenuating aberrant dysfunction disease.

Language: Английский

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Lipid droplets in health and disease

FEBS Letters, Journal Year: 2024, Volume and Issue: 598(10), P. 1113 - 1115

Published: May 1, 2024

Lipid droplets are ubiquitous organelles that can be formed by virtually all eukaryotic cells and fulfill central roles in lipid biology. They have a unique architecture enables them to store variable amounts of neutral lipids such as triacylglycerol sterol esters hydrophobic core compartment, which is protected from the aqueous cytosol an outer phospholipid monolayer. This monolayer houses droplet surface proteome comprises large number metabolism enzymes, mediate key steps biosynthesis turnover membrane storage [[1]]. In recent years, dysfunctions started recognized causes for disease, but underlying cell biological relationships molecular mechanisms still largely enigmatic [[2, 3]]. special issue FEBS Letters entitled "Lipid health disease" aims at providing broad view our current understanding functions physiological pathological states. Sixteen review articles highlight discoveries around life cycle, important technological advances field, insights into biology inherited acquired diseases related altered storage. endoplasmic reticulum (ER), where synthesized resident enzymes. These initially soluble within ER bilayer, eventually phase-separate higher concentrations lenses, grow addition further molecules ultimately bud [[4-6]]. Beside synthesizing proteins required biogenesis process enable control over lipidome, proteome, morphology, finally metabolic dynamics emerging organelle. A player formation conserved seipin protein. Pedro Carvalho colleagues describe mechanistic its partner [[7]]. Julia Mahamid provide overview numerous contributions electron microscopy techniques form function, ranging initial monolayer-based structures players complex [[8]]. Jennifer Sapia Stefano Vanni discuss Perspective article advancements challenges employing simulations contribute basis protein targeting [[9]]. Once formed, either acquiring ER, or fusing with other manner dependent on CIDE proteins, lipid-permeable inter-organelle bridge, reviewed detail Li Xu et al. [[10]]. When require expansion their systems during nutrient deprivation when ATP-production relies β-oxidation, consumed two alternative pathways: (a) droplet-specific autophagy termed lipophagy results degradation lysosomal lipases, (b) gradual mobilization fatty acids cytosolic lipases lipolysis. Access has tightly regulated ensure homeostasis under fluctuating conditions. human cells, members perilipin family regulating lipolysis, Alenka Čopič [[11]]. Mike Henne highlights discovery subpopulation baker's yeast carries specific set anti-lipolytic [[12]]. Xiaowen Duan David Savage Graphical Review forms lipodystrophy, non-alcoholic liver disease caused mutations involved formation, fusion, lipolysis [[13]]. Hanaa Hariri buffering excess mitigating lipotoxicity, well consequences prolonged overload [[14]]. Michele Wölk Maria Federova defining lipidome [[15]]. Antonio Barbosa Symeon Siniossoglou non-canonical synthesis pathway propose unappreciated functional relevance this remodeling [[16]]. Three contact site-based communication cellular [[17-19]]. Ludovic Enkler Anne Spang detailed bases between mitochondria mammals [[17]]. Vera Monteiro-Cardoso Francesca Giordano focus tripartite sites [[18]]. Aksel Saukko-Paavola Robin Klemm role organelle crosstalk transfer defined populations adaptation [[19]]. Arun John Peter Benoît Kornmann mass-tagging-based method tracking flux across borders living task been challenging past [[20]]. Eva Herker describes implications infectious focusing how viruses exploit genome replication virions [[21]]. Albert Pol droplet-associated perilipins, acyl-CoA synthases enabling flexibility cancer progression [[22]]. The community currently dissecting (patho-) cycle collective effort. At same time, unexpected new roles, particularly collaboration organelles, emerging, range pathologies being revealed. Exciting times clearly ahead editors hope collection may inspiration scientists addressing disease. Bohnert professor Organelle Communication Medical Faculty University Münster (Germany). She studied Molecular Medicine Albert-Ludwigs-University Freiburg (Germany), she received her PhD mitochondrial biogenesis. Her interest was sparked work postdoctoral researcher Weizmann Institute Science, Rehovot (Israel). group combines high-content screening approaches biochemistry identify unknown spatial organization metabolism, understand level. Bianca Schrul Biochemistry Saarland Biology Heidelberg (Germany) also PhD. After first appointment Göttingen Max-Planck-Institute Biophysical Chemistry (now Multidisciplinary Sciences), became postdoc Department Stanford (CA, USA). Here, discovered peroxisomes share machinery some constituents laid foundation establishing own research lab employs interdisciplinary uncover droplets, explore communicate lipid-metabolizing adapt changes.

Language: Английский

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Different patterns of lipid droplet and mitochondria contacts mediate lipid metabolism during T2DM-induced NAFLD

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 28, 2024

Mitochondrial function is crucial for hepatic lipid metabolism. Current research identifies two types of mitochondria based on their contact with droplets: peridroplet (PDM) and cytoplasmic (CM). This work aimed to investigate the alterations CM PDM in nonalcoholic fatty liver disease (NAFLD) induced by spontaneous type-2 diabetes mellitus (T2DM) db/db mice. It was found that insulin resistance increased both number size droplets enhancing accumulation free acids, which accompanied an increase contacts mitochondria. By examining oxidation states morphological characteristics PDM, different patterns tight between small purified were described. In CM, enhanced acid resulted elongated surrounded single responsible droplet consumption, while substrates synthesis promoted expansion assistance endoplasmic reticulum. These data show ways mitochondrial could provide new insights future

Language: Английский

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