scholarly journals Cardiac mitochondrial function depends on BUD23 mediated ribosome programming

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Matthew Baxter ◽  
Maria Voronkov ◽  
Toryn Poolman ◽  
Gina Galli ◽  
Christian Pinali ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Energy Demand ◽  
Critical Role ◽  
A549 Cells ◽  
Gc Content ◽  
High Energy ◽  
Mouse Development ◽  
Mitochondrial Content ◽  
And Function ◽  
External Stimuli

Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of Bud23 in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5’UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5’UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function.

scholarly journals Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation?

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 642 ◽  
Author(s):  
Dolan ◽  
Artioli ◽  
Pereira ◽  
Gualano
Keyword(s):  
Older Adults ◽  
Exercise Training ◽  
Energy Demand ◽  
Muscular Atrophy ◽  
Training Stimulus ◽  
Creatine Supplementation ◽  
The Elderly ◽  
High Energy ◽  
Age Related ◽  
And Function

Sarcopenia is characterized by a loss of muscle mass, quality, and function, and negatively impacts health, functionality, and quality of life for numerous populations, particularly older adults. Creatine is an endogenously produced metabolite, which has the theoretical potential to counteract many of the morphological and metabolic parameters underpinning sarcopenia. This can occur through a range of direct and indirect mechanisms, including temporal and spatial functions that accelerate ATP regeneration during times of high energy demand, direct anabolic and anti-catabolic functions, and enhanced muscle regenerating capacity through positively impacting muscle stem cell availability. Studies conducted in older adults show little benefit of creatine supplementation alone on muscle function or mass. In contrast, creatine supplementation as an adjunct to exercise training seems to augment the muscle adaptive response to the training stimulus, potentially through increasing capacity for higher intensity exercise, and/or by enhancing post-exercise recovery and adaptation. As such, creatine may be an effective dietary strategy to combat age-related muscle atrophy and sarcopenia when used to complement the benefits of exercise training.

scholarly journals ATM is activated by ATP depletion and modulates mitochondrial function through NRF1

2018 ◽  
Author(s):  
Hei-Man Chow ◽  
Aifang Cheng ◽  
Xuan Song ◽  
Mavis R. Swerdel ◽  
Ronald P. Hart ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Mitochondrial Function ◽  
Energy Demand ◽  
Nuclear Translocation ◽  
Physiological Activity ◽  
Mitochondrial Gene ◽  
High Energy ◽  
Atp Depletion ◽  
Nuclear Respiratory Factor ◽  
Atp Levels

AbstractWe have uncovered new insights into the symptoms of ataxia-telangiectasia (A-T). Neurons with high physiological activity, particularly cerebellar Purkinje cells, have large and dynamic ATP demands. Depletion of ATP generates reactive oxygen species that activate ATM (the A-T Mutated gene product). Activated in this way, but not by DNA damage, ATM phosphorylates nuclear respiratory factor-1 (NRF1). This leads to NRF1 dimerization, nuclear translocation and the upregulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells with ATM deficiency, resting ATP levels are normal, but cells replenish ATP poorly following surges in energy demand and chronic ATP insufficiency endangers cell survival. This is a particular problem for energy-intensive cells such as Purkinje cells, which degenerate in A-T. Our findings thus identify ATM as a guardian of mitochondrial output as well as genomic integrity, and suggest that alternate fuel sources may ameliorate A-T disease symptoms.SummaryOxidative stress, resulting from neuronal activity and depleted ATP levels, activates ATM, which phosphorylates NRF1, causing nuclear translocation and upregulation of mitochondrial gene expression. In ATM deficiency, ATP levels recover more slowly, particularly in active neurons with high energy demands.

scholarly journals Vitamin and Amino Acid Auxotrophy in Anaerobic Consortia Operating under Methanogenic Conditions

mSystems ◽  
2017 ◽  
Vol 2 (5) ◽  
Author(s):  
Valerie Hubalek ◽  
Moritz Buck ◽  
BoonFei Tan ◽  
Julia Foght ◽  
Annelie Wendeberg ◽  
...  
Keyword(s):  
Energy Conservation ◽  
Public Good ◽  
Microbial Communities ◽  
Energy Demand ◽  
High Energy ◽  
Microbial Interactions ◽  
Chemical Transformations ◽  
Pollutant Degradation ◽  
Toxic Compounds ◽  
And Function

ABSTRACT Microbial interactions between Archaea and Bacteria mediate many important chemical transformations in the biosphere from degrading abundant polymers to synthesis of toxic compounds. Two of the most pressing issues in microbial interactions are how consortia are established and how we can modulate these microbial communities to express desirable functions. Here, we propose that public goods (i.e., metabolites of high energy demand in biosynthesis) facilitate energy conservation for life under energy-limited conditions and determine the assembly and function of the consortia. Our report suggests that an understanding of public good dynamics could result in new ways to improve microbial pollutant degradation in anaerobic systems. Syntrophy among Archaea and Bacteria facilitates the anaerobic degradation of organic compounds to CH4 and CO2. Particularly during aliphatic and aromatic hydrocarbon mineralization, as in the case of crude oil reservoirs and petroleum-contaminated sediments, metabolic interactions between obligate mutualistic microbial partners are of central importance. Using micromanipulation combined with shotgun metagenomic approaches, we describe the genomes of complex consortia within short-chain alkane-degrading cultures operating under methanogenic conditions. Metabolic reconstruction revealed that only a small fraction of genes in the metagenome-assembled genomes encode the capacity for fermentation of alkanes facilitated by energy conservation linked to H2 metabolism. Instead, the presence of inferred lifestyles based on scavenging anabolic products and intermediate fermentation products derived from detrital biomass was a common feature. Additionally, inferred auxotrophy for vitamins and amino acids suggests that the hydrocarbon-degrading microbial assemblages are structured and maintained by multiple interactions beyond the canonical H2-producing and syntrophic alkane degrader-methanogen partnership. Compared to previous work, our report points to a higher order of complexity in microbial consortia engaged in anaerobic hydrocarbon transformation. IMPORTANCE Microbial interactions between Archaea and Bacteria mediate many important chemical transformations in the biosphere from degrading abundant polymers to synthesis of toxic compounds. Two of the most pressing issues in microbial interactions are how consortia are established and how we can modulate these microbial communities to express desirable functions. Here, we propose that public goods (i.e., metabolites of high energy demand in biosynthesis) facilitate energy conservation for life under energy-limited conditions and determine the assembly and function of the consortia. Our report suggests that an understanding of public good dynamics could result in new ways to improve microbial pollutant degradation in anaerobic systems.

scholarly journals Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1402
Author(s):  
Bledi Petriti ◽  
Pete A. Williams ◽  
Gerassimos Lascaratos ◽  
Kai-Yin Chau ◽  
David F. Garway-Heath
Keyword(s):  
Mitochondrial Function ◽  
Energy Demand ◽  
Redox State ◽  
High Energy ◽  
Therapeutic Modality ◽  
Retinal Ganglion ◽  
Atp Production ◽  
Potential Biomarker ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Susceptibility And Resistance

Glaucoma is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with age and the level of intraocular pressure (IOP). IOP reduction is currently the only therapeutic modality shown to slow glaucoma progression. However, patients still lose vision despite best treatment, suggesting that other factors confer susceptibility. Several studies indicate that mitochondrial function may underlie both susceptibility and resistance to developing glaucoma. Mitochondria meet high energy demand, in the form of ATP, that is required for the maintenance of optimum retinal ganglion cell (RGC) function. Reduced nicotinamide adenine dinucleotide (NAD+) levels have been closely correlated to mitochondrial dysfunction and have been implicated in several neurodegenerative diseases including glaucoma. NAD+ is at the centre of various metabolic reactions culminating in ATP production—essential for RGC function. In this review we present various pathways that influence the NAD+(H) redox state, affecting mitochondrial function and making RGCs susceptible to degeneration. Such disruptions of the NAD+(H) redox state are generalised and not solely induced in RGCs because of high IOP. This places the NAD+(H) redox state as a potential systemic biomarker for glaucoma susceptibility and progression; a hypothesis which may be tested in clinical trials and then translated to clinical practice.

scholarly journals The mitochondrial localized CISD-3.1/CISD-3.2 proteins are required to maintain normal germline structure and function in Caenorhabditis elegans

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245174
Author(s):  
Skylar D. King ◽  
Chipo F. Gray ◽  
Luhua Song ◽  
Ron Mittler ◽  
Pamela A. Padilla
Keyword(s):  
Mitochondrial Function ◽  
Reactive Oxygen ◽  
Wolfram Syndrome ◽  
Reproductive Organs ◽  
High Energy ◽  
Protein Family ◽  
Oxygen Homeostasis ◽  
Cell Death Pathway ◽  
Cell Niche ◽  
And Function

Reproductive organs and developing tissues have high energy demands that require metabolic functions primarily supported by mitochondria function. The highly conserved CISD/NEET iron-sulfur (Fe-S) protein family regulates iron and reactive oxygen homeostasis, both of which are important for mitochondrial function. Disruption of iron and reactive oxygen homeostasis typically leads to detrimental effects. In humans, CISD dysfunction is associated with human health issues including Wolfram syndrome 2. Using C. elegans, we previously determined that the cisd-1, cisd-3.1 and cisd-3.2 have an overlapping role in the regulation of physiological germline apoptosis through the canonical programmed cell death pathway. Here, we isolated the cisd-3.2(pnIs68) mutant that resulted in physiological and fitness defects including germline abnormalities that are associated with abnormal stem cell niche and disrupted formation of bivalent chromosomes. The cisd-3.2(pnIs68) mutation led to complete disruption of the cisd-3.2 gene expression and a decrease in expression of genetically intact cisd-1 and cisd-3.1 genes suggesting an indirect impact of the cisd-3.2(pnIs68) allele. The CISD-3.2 and CISD-3.1 proteins localize to the mitochondria in many tissues throughout development. The cisd-3.2(pnIs68) mutant displays phenotypes associated with mitochondrial dysfunction, including disruption of the mitochondrial network within the germline. These results further support the idea that the CISD protein family is required for mitochondrial function that supports important functions in animals including overall fitness and germline viability.

CPT1A-mediated Fat Oxidation, Mechanisms, and Therapeutic Potential

Endocrinology ◽  
2020 ◽  
Vol 161 (2) ◽  
Author(s):  
Isabel R Schlaepfer ◽  
Molishree Joshi
Keyword(s):  
Fatty Acids ◽  
Energy Demand ◽  
Therapeutic Potential ◽  
Critical Role ◽  
High Energy ◽  
The Body ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Rate Limiting

Abstract Energy homeostasis during fasting or prolonged exercise depends on mitochondrial fatty acid oxidation (FAO). This pathway is crucial in many tissues with high energy demand and its disruption results in inborn FAO deficiencies. More than 15 FAO genetic defects have been currently described, and pathological variants described in circumpolar populations provide insights into its critical role in metabolism. The use of fatty acids as energy requires more than 2 dozen enzymes and transport proteins, which are involved in the activation and transport of fatty acids into the mitochondria. As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria. The regulation of CPT1A is complex and has several layers that involve genetic, epigenetic, physiological, and nutritional modulators. It is ubiquitously expressed in the body and associated with dire consequences linked with genetic mutations, metabolic disorders, and cancers. This makes CPT1A an attractive target for therapeutic interventions. This review discusses our current understanding of CPT1A expression, its role in heath and disease, and the potential for therapeutic opportunities targeting this enzyme.

scholarly journals Cardiac mitochondrial network excitability: insights from computational analysis

2012 ◽  
Vol 302 (11) ◽  
pp. H2178-H2189 ◽  
Author(s):  
Lufang Zhou ◽  
Brian O'Rourke
Keyword(s):  
Energy Demand ◽  
Computational Models ◽  
Computational Analysis ◽  
Short Review ◽  
High Energy ◽  
Mitochondrial Network ◽  
Cardiac Mitochondria ◽  
Nonlinear Network ◽  
Messenger Molecules ◽  
And Function

In the heart, mitochondria form a regular lattice and function as a coordinated, nonlinear network to continuously produce ATP to meet the high-energy demand of the cardiomyocytes. Cardiac mitochondria also exhibit properties of an excitable system: electrical or chemical signals can spread within or among cells in the syncytium. The detailed mechanisms by which signals pass among individual elements (mitochondria) across the network are still not completely understood, although emerging studies suggest that network excitability might be mediated by the local diffusion and autocatalytic release of messenger molecules such as reactive oxygen species and/or Ca2+. In this short review, we have attempted to described recent advances in the field of cardiac mitochondrial network excitability. Specifically, we have focused on how mitochondria communicate with each other through the diffusion and regeneration of messenger molecules to initiate and propagate waves or oscillations, as revealed by computational models of mitochondrial network.

scholarly journals Critical role for free radicals on sprint exercise-induced CaMKII and AMPKα phosphorylation in human skeletal muscle

2013 ◽  
Vol 114 (5) ◽  
pp. 566-577 ◽  
Author(s):  
David Morales-Alamo ◽  
Jesús Gustavo Ponce-González ◽  
Amelia Guadalupe-Grau ◽  
Lorena Rodríguez-García ◽  
Alfredo Santana ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Energy Demand ◽  
Human Skeletal Muscle ◽  
Critical Role ◽  
Recovery Period ◽  
Muscle Metabolism ◽  
High Energy ◽  
Vastus Lateralis Muscle ◽  
Sprint Exercise

The extremely high energy demand elicited by sprint exercise is satisfied by an increase in O2 consumption combined with a high glycolytic rate, leading to a marked lactate accumulation, increased AMP-to-ATP ratio, and reduced NAD+/NADH.H+ and muscle pH, which are accompanied by marked Thr172 AMP-activated protein kinase (AMPK)-α phosphorylation during the recovery period by a mechanism not fully understood. To determine the role played by reactive nitrogen and oxygen species (RNOS) on Thr172-AMPKα phosphorylation in response to cycling sprint exercise, nine voluntary participants performed a single 30-s sprint (Wingate test) on two occasions: one 2 h after the ingestion of placebo and another after the intake of antioxidants (α-lipoic acid, vitamin C, and vitamin E) in a double-blind design. Vastus lateralis muscle biopsies were obtained before, immediately postsprint, and 30 and 120 min postsprint. Performance and muscle metabolism were similar during both sprints. The NAD+-to-NADH.H+ ratio was similarly reduced (84%) and the AMP-to-ATP ratio was similarly increased (×21-fold) immediately after the sprints. Thr286 Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Thr172-AMPKα phosphorylations were increased after the control sprint (with placebo) but not when the sprints were preceded by the ingestion of antioxidants. Ser485-AMPKα1/Ser491-AMPKα2 phosphorylation, a known inhibitory mechanism of Thr172-AMPKα phosphorylation, was increased only with antioxidant ingestion. In conclusion, RNOS play a crucial role in AMPK-mediated signaling after sprint exercise in human skeletal muscle. Antioxidant ingestion 2 h before sprint exercise abrogates the Thr172-AMPKα phosphorylation response observed after the ingestion of placebo by reducing CaMKII and increasing Ser485-AMPKα1/Ser491-AMPKα2 phosphorylation. Sprint performance, muscle metabolism, and AMP-to-ATP and NAD+-to-NADH.H+ ratios are not affected by the acute ingestion of antioxidants.

scholarly journals Metabolic Flexibility and Mitochondrial Bioenergetics in the Failing Heart. Therapeutic Approaches

2021 ◽  
Vol 31 (2) ◽  
pp. 269-282
Author(s):  
Mariana G. ROSCA
Keyword(s):  
Energy Demand ◽  
Ketone Bodies ◽  
Critical Role ◽  
Redox Status ◽  
High Energy ◽  
Energy Deficit ◽  
Metabolic Flexibility ◽  
Therapeutic Approaches ◽  
Atp Production ◽  
Reduced Ejection Fraction

Objectives. We will review current concepts regarding bioenergetic decline in heart failure (HF). In the heart, the high energy demand must be met by continuous ATP generation. Cardiac energetic machinery orchestrates the ATP production by using oxidation of multiple energetic substrates including fatty acids (FA), glucose, amino acids and ketone bodies. The normal heart is metabolically flexible and able to use different energetic fuels during physiologic or pathologic circumstances to better match the energy demand. Mitochondria have critical role in maintaining cardiac metabolic flexibility. Methods. We analyzed the scientific literature pertinent to HF and mitochondrial dysfunction. Results. The general consent is that metabolic fl exibility is lost in HF with either preserved or reduced ejection fraction (HFpEF and HFrEF, respectively). The prototype of HFpEF is the metabolic heart disease that is characterized by increased reliance on FA oxidation for ATP production and decreased glucose oxidation, while HFrEF presents a decreased FA oxidation. Both types of HF are associated with a decline in mitochondrial function leading to increased oxidative stress, abnormalities in the redox status and energy deficit. Conclusion. Current research is committed to find novel metabolically targeted therapeutic approaches to improve energetic metabolism and alleviate HF progression.

Abstract 11: Acquisition of Mitochondrial DNA Mutations Impairs Mitochondrial Function in Cardiac Progenitor Cells

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Amabel M Orogo ◽  
Eileen R Gonzalez ◽  
Dieter A Kubli ◽  
Anne N Murphy ◽  
Åsa B Gustafsson
Keyword(s):  
Progenitor Cells ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Energy Demand ◽  
Cell Activation ◽  
Critical Role ◽  
Chemotherapeutic Agents ◽  
Cardiac Progenitor Cells ◽  
Mtdna Mutations ◽  
Differentiation Medium

Activation of cardiac progenitor cells (CPCs) are critical for effective repair in response to pathologic injury. Stem cell activation and commitment involve increased energy demand and mitochondrial biogenesis. We have previously shown that incubation of c-kit+ CPCs in differentiation medium led to expansion of the mitochondrial network and lineage commitment. CPC function is reduced with age but the underlying mechanism is still unclear. Mitochondria contain their own DNA (mtDNA) which accumulates mutations over time that can impair mitochondrial function. In this study, we investigated the effects of acquiring mtDNA mutations on CPC proliferation, survival, and differentiation. We utilized a mouse model in which a mutation in the mtDNA polymerase gamma (POLGm/m) leads to accumulation of mtDNA mutations, mitochondrial dysfunction, and accelerated aging. Isolated CPCs from hearts of 2-month old POLGm/m mice had reduced proliferation and were more susceptible to oxidative stress and chemotherapeutic agents compared to WT CPCs. Incubation in differentiation medium resulted in fewer lineage committed POLGm/m CPCs compared to WT. In addition, the POLGm/m CPCs failed to activate mitochondrial biogenesis and did not increase levels of proteins involved in mitochondrial oxidative phosphorylation. We measured mitochondrial respiration with the Seahorse XF Analyzer and found that POLGm/m CPCs had undetectable oxygen consumption but still generated similar amounts of ATP as WT CPCs. Interestingly, POLGm/m CPCs produced increased amounts of l-lactate and were more sensitive to 2-deoxyglucose treatment, suggesting that these cells rely on glycolysis for energy production. Both WT and POLGm/m CPCs downregulated expression of glycolytic enzymes during differentiation. However, POLGm/m CPCs failed to undergo the metabolic transition from glycolysis to OXPHOS, which led to activation of cell death during differentiation. These data demonstrate that mitochondria play a critical role in CPC function, and accumulation of mtDNA mutations impairs CPC function and reduces their repair potential.

Sign in / Sign up

Export Citation Format

Share Document