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PubMed2006

Longitudinal study on mitochondrial effects of didanosine-tenofovir combination.

Tenofovir disoproxil fumarate (TDF) has been reported to be free of adverse effects on mitochondria. We evaluate the effects of the introduction of TDF in a didanosine (ddI)-based highly active antiretroviral therapy (HAART) on mitochondrial DNA (mtDNA) content, mitochondrial mass (MM), and cytochrome c oxidase (COX) activity of the oxidative phosphorylation (OXPHOS) system over a 12-month period. Forty-four asymptomatic HIV patients with undetectable viral load receiving a ddI-based HAART were recruited and switched to ddI plus TDF (ddI + TDF) and nevirapine (n = 22) or maintained with the same baseline ddIbased HAART scheme (n = 22). Peripheral blood mononuclear cells were obtained at 0, 6, and 12 months. COX activity and MM were determined by spectrophotometry and the mtDNA content by quantitative realtime PCR. The mtDNA content showed a progressive decrease over the 12-month period of the study for the two groups with respect to baseline, with such a decrease statistically significant only in the ddI + TDF group (55% decrease, p < 0.001). In addition, the decrease of mtDNA content over time was statistically different between both groups (p < 0.001). Consistently, MM and COX activity decreased significantly at 12 months with respect to baseline only in the ddI < TDF group (28% decrease for MM, p < 0.05; 47% decrease for COX activity, p < 0.001). We conclude that switching to a HAART regimen containing ddI + TDF is associated with evolutive mitochondrial damage expressed as mtDNA depletion, loss of MM, and decrease in COX efficiency. The particular relevance of either ddI, TDF, or any interaction between them in such a mitochondrial dysfunction remains to be established.

Adenine↗

PubMed2003

Disorders of mitochondrial protein synthesis.

Mitochondrial tRNA gene mutations, including heteroplasmic deletions that eliminate one or more tRNAs, as well as point mutations that may be either hetero- or homoplasmic, are associated with a wide spectrum of human diseases. These range from rare syndromic disorders to cases of commoner conditions such as sensorineural deafness or cardiomyopathy. The disease spectrum of mutations in a given gene, or even a single mutation, may vary, but some patterns are evident, for example the prominence of cardiomyopathy resulting from tRNAIle defects, or of MERFF-like disease from tRNALys defects. Molecular studies of many laboratories have reached a consensus on molecular mechanisms associated with these mutations. Although precise details vary, loss of translational function of the affected tRNA(s) seems to be the final outcome, whether by impaired pre-tRNA processing, half-life, base-modification or aminoacylation. However, a mechanistic understanding of the consequences of this for the assembly and function of the mitochondrial OXPHOS complexes and for the physiological functions of the affected tissues is still a distant prospect. This review presents some views of possible downstream consequences of specific tRNA deficiencies.

Base Sequence↗

PubMed2005

Frataxin interacts functionally with mitochondrial electron transport chain proteins.

Frataxin deficiency is the main cause of Friedreich ataxia, an autosomal recessive neurodegenerative disorder. Frataxin function in mitochondria has not been fully explained yet. In this work, we show that Saccharomyces cerevisiae frataxin orthologue Yfh1p interacts physically with succinate dehydrogenase complex subunits Sdh1p and Sdh2p of the yeast mitochondrial electron transport chain and also with electron transfer flavoprotein complex ETFalpha and ETFbeta subunits from the electron transfer flavoprotein complex. Genetic synthetic interaction experiments confirmed a functional relationship between YFH1 and succinate dehydrogenase genes SDH1 and SDH2. We also demonstrate a physical interaction between human frataxin and human succinate dehydrogenase complex subunits, suggesting also a key role of frataxin in the mitochondrial electron transport chain in humans. Consequently, we suggest a direct participation of the respiratory chain in the pathogenesis of the Friedreich ataxia, which we propose to be considered as an OXPHOS disease.

Electron Transport Chain Complex Proteins↗

PubMed2026

Disruption of mitonuclear coadaptation and compensatory evolution after an extreme dietary shift in carnivorous butterflies.

Mitochondrial function depends on tight coordination between mitochondrial and nuclear genomes, which requires long-term coevolution to maintain mitonuclear coadaptation. While mitonuclear incompatibility is typically studied in the context of hybridization, other evolutionary scenarios that may disrupt coadaptation between the two genomes remain less explored. Here, we propose that extreme ecological niche shifts may disrupt mitonuclear coadaptation, which we test in carnivorous Miletinae butterflies with an extreme dietary transition. By generating high-quality genome assemblies, we found that Miletinae exhibit extensive chromosomal rearrangements. Comparative phylogenomic analyses revealed a striking asymmetric mitonuclear evolutionary response: Miletinae exhibit elevated mitochondrial nucleotide substitution rates compared to phytophagous relatives, whereas nuclear rates remain stable. This shift reverses the typical lepidopteran pattern where nuclear rates exceed mitochondrial rates. Interestingly, this mitochondrial acceleration is driven primarily by relaxed purifying selection rather than positive selection. To sustain mitochondrial function, the nuclear genome of Miletinae underwent pervasive, multilayered compensatory evolution. We detected strong signatures of positive selection and accelerated evolution in nuclear genes directly interacting with mitochondrial components across oxidative phosphorylation (OXPHOS) complexes, the mitochondrial translation, and replication and transcription machinery. Furthermore, this nuclear compensatory response extends to systems governing mitochondrial homeostasis, including protein quality control and RNA degradation and stabilization. Our results support a model in which extreme ecological transitions can disrupt ancestral mitonuclear coadaptation and promote the emergence of a new coadapted state through systemic nuclear compensation. This study broadens the conceptual framework of mitonuclear coevolution and highlights its role in facilitating evolutionary persistence after major ecological shifts.

Animals↗

PubMed2005

Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation.

A family presented with three affected children with Leigh syndrome, a progressive neurodegenerative disorder. Analysis of the OXPHOS complexes in muscle of two affected patients showed an increase in activity of pyruvate dehydrogenase and a decrease of complex V activity. Mutation analysis revealed the T9176C mutation in the mtATPase 6 gene (OMIM 516060) and the mutation load was above 90% in the patients. Unaffected maternal relatives were tested for carrier-ship and one of them, with a mutation load of 55% in blood, was pregnant with her first child. The possibility of prenatal diagnosis was evaluated. The main problem was the lack of data on genotype-phenotype associations for the T9176C mutation and on variation of the mutation percentage in tissues and in time. Therefore, multiple tissues of affected and unaffected carriers were analysed. Eventually, prenatal diagnosis was offered with understanding by the couple that there could be considerable uncertainty in the interpretation of the results. Prenatal diagnosis was carried out twice on cultured and uncultured chorion villi and amniotic fluid cells. The result was a mutation percentage just below the assumed threshold of expression (90%). The couple decided to continue the pregnancy and an apparently healthy child was born with an as yet unclear prognosis. This is the first prenatal diagnosis for a carrier of the T9176C mutation. Prenatal diagnosis for this mutation is technically reliable, but the prognostic predictions are not straightforward.

Child↗

PubMed1995

Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle.

Several reports have shown that individual mitochondrial DNA (mtDNA) deletions accumulate with age. However, the overall extent of somatic mtDNA damage with age remains unclear. We have utilized full-length PCR to concurrently screen for multiple mtDNA rearrangements in total DNA extracted from skeletal muscle derived from physiologically normal individuals (n = 35). This revealed that both the number and variety of mtDNA rearrangements increases dramatically between young and old individuals (P < 0.0001). We further examined the mtDNA from both the younger and older subjects by Southern blot analysis and observed an age-related increase in mtDNA(s) comparable in size to mtDNA products unique to patients with known mtDNA deletions. These data imply that a wide spectrum of mtDNA rearrangements accumulate in old individuals, which correlates with the marked age related decrease in OXPHOS capacity observed in post-mitotic tissues.

Adult↗

PubMed2006

Production of transmitochondrial cybrids containing naturally occurring pathogenic mtDNA variants.

The human mitochondrial genome (mtDNA) encodes polypeptides that are critical for coupling oxidative phosphorylation. Our detailed understanding of the molecular processes that mediate mitochondrial gene expression and the structure-function relationships of the OXPHOS components could be greatly improved if we were able to transfect mitochondria and manipulate mtDNA in vivo. Increasing our knowledge of this process is not merely of fundamental importance, as mutations of the mitochondrial genome are known to cause a spectrum of clinical disorders and have been implicated in more common neurodegenerative disease and the ageing process. In organellar or in vitro reconstitution studies have identified many factors central to the mechanisms of mitochondrial gene expression, but being able to investigate the molecular aetiology of a limited number of cell lines from patients harbouring mutated mtDNA has been enormously beneficial. In the absence of a mechanism for manipulating mtDNA, a much larger pool of pathogenic mtDNA mutations would increase our knowledge of mitochondrial gene expression. Colonic crypts from ageing individuals harbour mutated mtDNA. Here we show that by generating cytoplasts from colonocytes, standard fusion techniques can be used to transfer mtDNA into rapidly dividing immortalized cells and, thereby, respiratory-deficient transmitochondrial cybrids can be isolated. A simple screen identified clones that carried putative pathogenic mutations in MTRNR1, MTRNR2, MTCOI and MTND2, MTND4 and MTND6. This method can therefore be exploited to produce a library of cell lines carrying pathogenic human mtDNA for further study.

Cell Fusion↗

PubMed2005

Human muscle gene expression responses to endurance training provide a novel perspective on Duchenne muscular dystrophy.

Global gene expression profiling is used to generate novel insight into a variety of disease states. Such studies yield a bewildering number of data points, making it a challenge to validate which genes specifically contribute to a disease phenotype. Aerobic exercise training represents a plausible model for identification of molecular mechanisms that cause metabolic-related changes in human skeletal muscle. We carried out the first transcriptome-wide characterization of human skeletal muscle responses to 6 wk of supervised aerobic exercise training in 8 sedentary volunteers. Biopsy samples before and after training allowed us to identify approximately 470 differentially regulated genes using the Affymetrix U95 platform (80 individual hybridization steps). Gene ontology analysis indicated that extracellular matrix and calcium binding gene families were most up-regulated after training. An electronic reanalysis of a Duchenne muscular dystrophy (DMD) transcript expression dataset allowed us to identify approximately 90 genes modulated in a nearly identical fashion to that observed in the endurance exercise dataset. Trophoblast noncoding RNA, an interfering RNA species, was the singular exception-being up-regulated by exercise and down-regulated in DMD. The common overlap between gene expression datasets may be explained by enhanced alpha7beta1 integrin signaling, and specific genes in this signaling pathway were up-regulated in both datasets. In contrast to these common features, OXPHOS gene expression is subdued in DMD yet elevated by exercise, indicating that more than one major mechanism must exist in human skeletal muscle to sense activity and therefore regulate gene expression. Exercise training modulated diabetes-related genes, suggesting our dataset may contain additional and novel gene expression changes relevant for the anti-diabetic properties of exercise. In conclusion, gene expression profiling after endurance exercise training identified a range of processes responsible for the physiological remodeling of human skeletal muscle tissue, many of which were similarly regulated in DMD. Furthermore, our analysis demonstrates that numerous genes previously suggested as being important for the DMD disease phenotype may principally reflect compensatory integrin signaling.

Biopsy↗

PubMed2025

Regulation of airway fumarate by host and pathogen promotes S. aureus pneumonia.

Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.

Journal Article↗

PubMed2005

The impact of mitochondrial genetics on male infertility.

Summary Human mitochondrial DNA (mtDNA) encodes 13 of the polypeptides associated with the process of oxidative phosphorylation (OXPHOS), the cells most important ATP generating pathway. Until recently, the effects of mtDNA rearrangements on male fertility have been largely ignored. However, it is becoming increasingly evident that both point mutations and large-scale deletions may have an impact on sperm motility and morphology. We discuss the implications of these rearrangements in the context of the clinical setting. We further discuss the possible consequences resulting from the transmission of sperm mtDNA deletions to the offspring. The role of nucleo-cytoplasmic interaction is investigated in the context of nuclear transcription and replication factors that regulate mtDNA transcription and replication.

Animals↗

PubMed2005

On the relevance of mitochondrial fusions for the accumulation of mitochondrial deletion mutants: a modelling study.

The molecular mechanisms underlying the aging process are still unclear, but the clonal accumulation of mitochondrial deletion mutants is one of the prime candidates. An important question for the mitochondrial theory of aging is to discover how defective organelles might be selected at the expense of wild-type mitochondria. We propose that mitochondrial fission and fusion events are of critical importance for resolving this apparent contradiction. We show that the occurrence of fusions removes the problems associated with the idea that smaller DNA molecules accumulate because they replicate in a shorter time--the survival of the tiny (SOT) hypothesis. Furthermore, stochastic simulations of mitochondrial replication, mutation and degradation show that two important experimental findings, namely the overall low mosaic pattern of oxidative phosphorylation (OXPHOS) impaired cells in old organisms and the distribution of deletion sizes, can be reproduced and explained by this hypothesis. Finally, we make predictions that can be tested experimentally to further verify our explanation for the age-related accumulation of mitochondrial deletion mutants.

Aging↗

PubMed1992

Mitochondrial genetics: a paradigm for aging and degenerative diseases?

Studies of diseases caused by mitochondrial DNA mutations suggest that a variety of degenerative processes may be associated with defects in oxidative phosphorylation (OXPHOS). Application of this hypothesis has provided new insights into such diverse clinical problems as ischemic heart disease, late-onset diabetes, Parkinson's disease, Alzheimer's disease, and aging.

Aging↗

PubMed1996

Crosstalk between nuclear and mitochondrial genomes.

This review focuses on molecular mechanisms that underlie the communication between the nuclear and mitochondrial genomes in eukaryotic cells. These genomes interact in at least two ways. First, they contribute essential subunit polypeptides to important mitochondrial proteins; second, they collaborate in the synthesis and assembly of these proteins. The first type of interaction is important for the regulation of oxidative energy production. Isoforms of the nuclear-coded subunits of cytochrome c oxidase affect the catalytic functions of its mitochondrially coded subunits. These isoforms are differentially regulated by environmental and developmental signals and probably allow tissues to adjust their energy production to different energy demands. The second type of interaction requires the bidirectional flow of information between the nucleus and the mitochondrion. Communication from the nucleus to the mitochondrion makes use of proteins that are translated in the cytosol and imported by the mitochondrion. Communication from the mitochondrion to the nucleus involves metabolic signals and one or more signal transduction pathways that function across the inner mitochondrial membrane. An understanding of both types of interaction is important for an understanding of OXPHOS diseases and aging.

Cell Nucleus↗

PubMed2005

A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.

Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

Aging↗

PubMed2026

Loss of ovarian function and estrogen therapy remodel the brain's synaptic and metabolic proteome.

Menopause is linked to cognitive decline and reduced brain metabolism, whereas estrogen (E2) therapy has been shown to mitigate these effects. Understanding the molecular mechanisms by which ovarian hormones and E2 influence neuroprotection is essential for developing strategies to maintain brain health in women. In this study, we examined how the loss of ovarian hormones, with or without E2 treatment, affects the brain proteome and mitochondrial energy production in aged female C57BL/6J mice (36-40 wk). The mice underwent sham or ovariectomy (OVX) surgery and were fed a high-fat diet for 10 wk; 6 wk after surgery, OVX mice received either sesame oil or E2 treatment for 4 wk. Proteomic analysis of brain homogenates revealed 4,992 proteins regulated by E2, with pathway analysis showing increased signaling proteins related to synaptogenesis. OVX reduced proteins involved in synaptic function, branched-chain amino acid and ketone metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation (Complexes I, IV, and V), whereas E2 restored protein expression within these pathways. Despite alterations in OxPhos proteins, basal and state 3 mitochondrial respiration remained unchanged, although notable impairments in Complex IV enzymatic activity were apparent in OVX, which were partially reversed by E2 treatment. Overall, these results indicate that E2 supports brain health by maintaining proteins crucial for synaptic integrity and metabolism, while partially offsetting the functional decline in mitochondrial bioenergetics associated with menopause.NEW & NOTEWORTHY The menopausal transition, marked by declining estrogen levels, alters cognition, neuroplasticity, and brain metabolism. Although hormone therapy benefits cognition, its molecular effects on the brain remain unclear. Using whole-brain proteomics in aged ovariectomized (OVX) mice with or without estrogen treatment, we found that OVX reduced proteins linked to synaptogenesis and mitochondrial metabolism. Estrogen reversed these declines, restoring pathways supporting neuronal signaling and energy balance, identifying estrogen-regulated proteins critical for maintaining brain health during menopause.

Animals↗

PubMed2005

Eliminating the Ant1 isoform produces a mouse with CPEO pathology but normal ocular motility.

PURPOSE: The adenine nucleotide transporter 1 gene (ANT1) encodes an inner mitochondrial membrane protein that transports ATP into the cell. Mutations within ANT1 produce a syndrome of chronic progressive external ophthalmoplegia (CPEO) in humans. Ant1 knockout (Ant1-/-) mice develop cardiomyopathy and mitochondrial myopathy of limb muscles. Because the extraocular muscles (EOM) are preferentially affected in human CPEO, the objective of this study was to determine whether Ant1-/- mice also exhibit an EOM mitochondrial myopathy. METHODS: ANT isoform expression of isolated EOMs, EOM morphology and mitochondrial content, mitochondrial structure and function, ocular motility in intact mice, and contractile performance in isolated muscle preparations were examined. RESULTS: Ant1-/- EOMs had the typical appearance of mitochondrial myopathy, including increase in mitochondrial size, number, and oxidative phosphorylation (OXPHOS) staining. However, there were no measurable ocular motor abnormalities in intact Ant1-/- mice, and their isolated EOMs did not show evidence of increased fatigability. EOMs of wild-type mice exhibited higher levels of Ant2 mRNA compared with hindlimb muscle, which may compensate for the Ant1 loss in mutant mouse EOMs and account for the normal EOM function. CONCLUSIONS: The Ant1-/- mice provide a model in which to study CPEO pathology and compensatory mechanisms.

Adenine Nucleotide Translocator 1↗

PubMed2006

Effect of soluble nickel on cellular energy metabolism in A549 cells.

Iron is an essential nutrient to most organisms, and is actively involved in oxygen delivery, electron transport, DNA synthesis, and many other biochemical reactions important for cell survival. We previously reported that nickel (Ni) ion exposure decreases cellular iron level and converts cytosolic aconitase (c-aconitase) to iron-regulatory protein-1 in A549 cells (Chen H, Davidson T, Singleton S, Garrick MD, Costa M. Toxicol Appl Pharmacol 206:275-287, 2005). Here, we further investigated the effect of Ni ion exposure on the activity of mitochondrial iron-sulfur (Fe-S) enzymes and cellular energy metabolism. We found that acute Ni ion treatment up to 1 mM exhibits minimal toxicity in A549 cells. Ni ion treatment decreases the activity of several Fe-S enzymes related to cellular energy metabolism, including mitochondrial aconitase (m-aconitase), succinate dehydrogenase (SDH), and NADH:ubiquinone oxidoreductase (complex I). Low doses of Ni ion for 4 weeks resulted in an increased cellular glycolysis and NADH to NAD+ (NADH/NAD+) ratio, although glycolysis was inhibited at higher levels. Collectively, our results show that Ni ions decrease the activity of cellular iron (Fe)-containing enzymes, inhibit oxidative phosphorylation (OxPhos), and increase cellular glycolytic activity. Since increased glycolysis is one of the fundamental alterations of energy metabolism in cancer cells (the Warburg effect), the inhibition of Fe-S enzymes and subsequent changes in cellular energy metabolism caused by Ni ions may play an important role in Ni carcinogenesis.

Cell Line, Tumor↗

PubMed2024

Proteomic analysis illustrates the potential involvement of dysregulated ribosome-related pathways and disrupted metabolism during retinoic acid-induced cleft palate development.

Recent studies have unveiled disrupted metabolism in the progression of cleft palate (CP), a congenital anomaly characterized by defective fusion of facial structures. Nonetheless, the precise composition of this disrupted metabolism remains elusive, prompting us to identify these components and elucidate primary metabolic irregularities contributing to CP pathogenesis. We established a murine CP model by retinoic acid (RA) treatment and analyzed control and RA-treated embryonic palatal tissues by LC-MS-based proteomic approach. We identified 220 significantly upregulated and 224 significantly downregulated proteins. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that these differentially expressed proteins (DEPs) were involved in translation, ribosome assembly, mitochondrial function, mRNA binding, as well as key metabolic pathways like oxidative phosphorylation (OXPHOS), glycolysis/gluconeogenesis, and amino acid biosynthesis. These findings suggest that dysregulated ribosome-related pathways and disrupted metabolism play a critical role in CP development. Protein-protein interaction analysis using the STRING database revealed a tightly connected network of DEPs. Furthermore, we identified the top 10 hub proteins in CP using the Cytohubba plugin in Cytoscape. These hub proteins, including RPL8, RPS11, ALB, PA2G4, RPL23, RPS6, CCT7, EGFR, HSPD1, and RPS28, are potentially key regulators of CP pathogenesis. In conclusion, our comprehensive proteomic analysis provides insights into the molecular alterations associated with RA-induced CP in Kun Ming mice. These findings suggest potential therapeutic targets and pathways to understand and prevent congenital craniofacial anomalies.

Cleft Palate↗