-
International Journal of Molecular... Aug 2020As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of... (Review)
Review
As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers. In this review, we summarize mitochondrial dysfunction induced by these alterations that promote human cancers.
Topics: Apoptosis; DNA, Mitochondrial; Energy Metabolism; Humans; Mitochondria; Mutation; Neoplasms; Oxidation-Reduction; Oxidative Stress
PubMed: 32764295
DOI: 10.3390/ijms21165598 -
Autophagy Aug 2021Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from... (Review)
Review
Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging and mice.
Topics: Aging; Animals; Autophagy; Cognition; Humans; Longevity; Mitochondria; Spermidine
PubMed: 34105442
DOI: 10.1080/15548627.2021.1933299 -
Mitochondrion May 2023Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery. Salugenesis is the automatic,... (Review)
Review
Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery. Salugenesis is the automatic, evolutionarily conserved, ontogenetic sequence of molecular, cellular, organ system, and behavioral changes that is used by living systems to heal. It is a whole-body process that begins with mitochondria and the cell. The stages of salugenesis define a circle that is energy- and resource-consuming, genetically programmed, and environmentally responsive. Energy and metabolic resources are provided by mitochondrial and metabolic transformations that drive the cell danger response (CDR) and create the three phases of the healing cycle: Phase 1-Inflammation, Phase 2-Proliferation, and Phase 3-Differentiation. Each phase requires a different mitochondrial phenotype. Without different mitochondria there can be no healing. The rise and fall of extracellular ATP (eATP) signaling is a key driver of the mitochondrial and metabolic reprogramming required to progress through the healing cycle. Sphingolipid and cholesterol-enriched membrane lipid rafts act as rheostats for tuning cellular sensitivity to purinergic signaling. Abnormal persistence of any phase of the CDR inhibits the healing cycle, creates dysfunctional cellular mosaics, causes the symptoms of chronic disease, and accelerates the process of aging. New research reframes the rising tide of chronic disease around the world as a systems problem caused by the combined action of pathogenic triggers and anthropogenic factors that interfere with the mitochondrial functions needed for healing. Once chronic pain, disability, or disease is established, salugenesis-based therapies will start where pathogenesis-based therapies end.
Topics: Humans; Mitochondria; Energy Metabolism; Chronic Disease; Signal Transduction
PubMed: 37120082
DOI: 10.1016/j.mito.2023.04.003 -
Biochemical Pharmacology Dec 2020In the past mitochondria were considered as the "powerhouse" of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative... (Review)
Review
In the past mitochondria were considered as the "powerhouse" of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative phosphorylation. However, based on the current knowledge, mitochondria play several other cellular functions, including participation in calcium homeostasis, generation of free radicals and oxidative species, triggering/regulation of apoptosis, among others. Additionally, previous discoveries recognized mitochondria as highly dynamic structures, which undergo morphological alterations resulting in long or short fragments inside the living cells. This highly regulated process was referred as mitochondrial dynamics and involves mitochondrial fusion and fission. Thus, the number of mitochondria and the morphology of mitochondrial networks depend on the mitochondrial dynamics, biogenesis, and mitophagy. In each cell, there is a delicate balance between fusion and fission to allow the maintenance of appropriate mitochondrial functions. It has been proposed that the fusion and fission dynamics process controls cell cycle, metabolism, and survival, being implicated in a wide range of physiological and pathological conditions. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). Interestingly, there is growing evidence proposing that tumor cells modify the mitochondrial dynamics rheostat in order to gain proliferative and survival advantages. Increased mitochondrial fission has been reported in several types of human cancer cells (melanoma, ovarian, breast, lung, thyroid, glioblastoma, and others) and some studies have reported a possible direct correlation between increased mitochondrial fusion and chemoresistance of tumor cells. Here, the current knowledge about alterations of mitochondrial dynamics in cancer will be reviewed and its potential as a target for adjuvant cancer chemotherapy will be discussed.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Mitochondria; Mitochondrial Dynamics; Neoplasms
PubMed: 33058754
DOI: 10.1016/j.bcp.2020.114282 -
Cells Mar 2021BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1... (Review)
Review
BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.
Topics: Animals; Antineoplastic Agents; Basic-Leucine Zipper Transcription Factors; Cell Movement; Energy Metabolism; Gene Expression Regulation, Neoplastic; Humans; Mitochondria; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasms; Signal Transduction
PubMed: 33809182
DOI: 10.3390/cells10030634 -
International Journal of Molecular... Dec 2021Neurons rely mostly on mitochondria for the production of ATP and Ca homeostasis. As sub-compartmentalized cells, they have different pools of mitochondria in each... (Review)
Review
Neurons rely mostly on mitochondria for the production of ATP and Ca homeostasis. As sub-compartmentalized cells, they have different pools of mitochondria in each compartment that are maintained by a constant mitochondrial turnover. It is assumed that most mitochondria are generated in the cell body and then travel to the synapse to exert their functions. Once damaged, mitochondria have to travel back to the cell body for degradation. However, in long cells, like motor neurons, this constant travel back and forth is not an energetically favourable process, thus mitochondrial biogenesis must also occur at the periphery. Ca and ATP levels are the main triggers for mitochondrial biogenesis in the cell body, in a mechanism dependent on the Peroxisome-proliferator-activated γ co-activator-1α-nuclear respiration factors 1 and 2-mitochondrial transcription factor A (PGC-1α-NRF-1/2-TFAM) pathway. However, even though of extreme importance, very little is known about the mechanisms promoting mitochondrial biogenesis away from the cell body. In this review, we bring forward the evoked mechanisms that are at play for mitochondrial biogenesis in the cell body and periphery. Moreover, we postulate that mitochondrial biogenesis may vary locally within the same neuron, and we build upon the hypotheses that, in the periphery, local protein synthesis is responsible for giving all the machinery required for mitochondria to replicate themselves.
Topics: Animals; Humans; Mitochondria; Mitochondrial Proteins; Neurons; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 34884861
DOI: 10.3390/ijms222313059 -
Mitochondrion Sep 2021There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the... (Review)
Review
There is growing scientific interest to develop scalable biological measures that capture mitochondrial (dys)function. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). It has been proposed that the number of mtDNA copies per cell (mtDNA copy number; mtDNAcn) reflects mitochondrial health. The common availability of stored DNA material or existing DNA sequencing data, especially from blood and other easy-to-collect samples, has made its quantification a popular approach in clinical and epidemiological studies. However, the interpretation of mtDNAcn is not univocal, and either a reduction or elevation in mtDNAcn can indicate dysfunction. The major determinants of blood-derived mtDNAcn are the heterogeneous cell type composition of leukocytes and platelet abundance, which can change with time of day, aging, and with disease. Hematopoiesis is a likely driver of blood mtDNAcn. Here we discuss the rationale and available methods to quantify mtDNAcn, the influence of blood cell type variations, and consider important gaps in knowledge that need to be resolved to maximize the scientific value around the investigation of blood mtDNAcn.
Topics: DNA Copy Number Variations; DNA, Mitochondrial; Humans; Mitochondria
PubMed: 34157430
DOI: 10.1016/j.mito.2021.06.010 -
Journal of Translational Medicine Mar 2023The incidence and mortality of gastric cancer ranks fifth and fourth worldwide among all malignancies, respectively. Accumulating evidences have revealed the close...
BACKGROUND
The incidence and mortality of gastric cancer ranks fifth and fourth worldwide among all malignancies, respectively. Accumulating evidences have revealed the close relationship between mitochondrial dysfunction and the initiation and progression of stomach cancer. However, rare prognostic models for mitochondrial-related gene risk have been built up in stomach cancer.
METHODS
In current study, the expression and prognostic value of mitochondrial-related genes in stomach adenocarcinoma (STAD) patients were systematically analyzed to establish a mitochondrial-related risk model based on available TCGA and GEO databases. The tumor microenvironment (TME), immune cell infiltration, tumor mutation burden, and drug sensitivity of gastric adenocarcinoma patients were also investigated using R language, GraphPad Prism 8 and online databases.
RESULTS
We established a mitochondrial-related risk prognostic model including NOX4, ALDH3A2, FKBP10 and MAOA and validated its predictive power. This risk model indicated that the immune cell infiltration in high-risk group was significantly different from that in the low-risk group. Besides, the risk score was closely related to TME signature genes and immune checkpoint molecules, suggesting that the immunosuppressive tumor microenvironment might lead to poor prognosis in high-risk groups. Moreover, TIDE analysis demonstrated that combined analysis of risk score and immune score, or stromal score, or microsatellite status could more effectively predict the benefit of immunotherapy in STAD patients with different stratifications. Finally, rapamycin, PD-0325901 and dasatinib were found to be more effective for patients in the high-risk group, whereas AZD7762, CEP-701 and methotrexate were predicted to be more effective for patients in the low-risk group.
CONCLUSIONS
Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.
Topics: Humans; Stomach Neoplasms; Tumor Microenvironment; Mitochondria; Adenocarcinoma; Prognosis
PubMed: 36915111
DOI: 10.1186/s12967-023-04033-6 -
Ageing Research Reviews Sep 2019Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis,... (Review)
Review
Genetic and pharmacological intervention studies have identified evolutionarily conserved and functionally interconnected networks of cellular energy homeostasis, nutrient-sensing, and genome damage response signaling pathways, as prominent regulators of longevity and health span in various species. Mitochondria are the primary sites of ATP production and are key players in several other important cellular processes. Mitochondrial dysfunction diminishes tissue and organ functional performance and is a commonly considered feature of the aging process. Here we review the evidence that through reciprocal and multilevel functional interactions, mitochondria are implicated in the lifespan modulation function of these pathways, which altogether constitute a highly dynamic and complex system that controls the aging process. An important characteristic of these pathways is their extensive crosstalk and apparent malleability to modification by non-invasive pharmacological, dietary, and lifestyle interventions, with promising effects on lifespan and health span in animal models and potentially also in humans.
Topics: Aging; Animals; DNA Repair; Energy Metabolism; Humans; Longevity; Mitochondria; Signal Transduction
PubMed: 31415807
DOI: 10.1016/j.arr.2019.100940 -
American Journal of Physiology.... Jul 2022Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily conserved process and aberrant pyruvate metabolism is associated with and contributes to... (Review)
Review
Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily conserved process and aberrant pyruvate metabolism is associated with and contributes to numerous human metabolic disorders including diabetes, cancer, and heart disease. As a product of glycolysis, pyruvate is primarily generated in the cytosol before being transported into the mitochondrion for further metabolism. Pyruvate entry into the mitochondrial matrix is a critical step for efficient generation of reducing equivalents and ATP and for the biosynthesis of glucose, fatty acids, and amino acids from pyruvate. However, for many years, the identity of the carrier protein(s) that transported pyruvate into the mitochondrial matrix remained a mystery. In 2012, the molecular-genetic identification of the mitochondrial pyruvate carrier (MPC), a heterodimeric complex composed of protein subunits MPC1 and MPC2, enabled studies that shed light on the many metabolic and physiological processes regulated by pyruvate metabolism. A better understanding of the mechanisms regulating pyruvate transport and the processes affected by pyruvate metabolism may enable novel therapeutics to modulate mitochondrial pyruvate flux to treat a variety of disorders. Herein, we review our current knowledge of the MPC, discuss recent advances in the understanding of mitochondrial pyruvate metabolism in various tissue and cell types, and address some of the outstanding questions relevant to this field.
Topics: Anion Transport Proteins; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Pyruvic Acid
PubMed: 35635330
DOI: 10.1152/ajpendo.00074.2022