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International Journal of Molecular... Dec 2023Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification... (Review)
Review
Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification ultimately regulates the stability or degradation of the targeted proteins. Ubiquitination is mediated by three different classes of enzymes: the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes and, most importantly, the E3 ubiquitin ligases. E3 ligases are responsible for the final step of the ubiquitin cascade, interacting directly with the target proteins. E3 ligases can also be involved in DNA repair, cell cycle regulation and response to stress; alteration in their levels can be involved in oncogenic transformation and cancer progression. Of all the six hundred E3 ligases of the human genome, only three of them are specific to the mitochondrion: MARCH5, RNF185 and MUL1. Their alterations (that reflect on the alteration of the mitochondria functions) can be related to cancer progression, as underlined by the increasing research performed in recent years on these three mitochondrial enzymes. This review will focus on the function and mechanisms of the mitochondrial E3 ubiquitin ligases, as well as their important targets, in cancer development and progression, also highlighting their potential use for cancer therapy.
Topics: Humans; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitin; Proteins; Neoplasms; Mitochondria; Ubiquitin-Conjugating Enzymes; Mitochondrial Proteins
PubMed: 38139010
DOI: 10.3390/ijms242417176 -
Biomolecules Dec 2023Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis... (Review)
Review
Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
Topics: Animals; Neurodegenerative Diseases; Mitochondria; Mitochondrial Diseases; Aging; Unfolded Protein Response
PubMed: 38136659
DOI: 10.3390/biom13121789 -
Biochimica Et Biophysica Acta.... Oct 2023The endoplasmic reticulum (ER) plays a key role in the regulation of protein folding, lipid synthesis, calcium homeostasis, and serves as a primary site of sphingolipid...
The endoplasmic reticulum (ER) plays a key role in the regulation of protein folding, lipid synthesis, calcium homeostasis, and serves as a primary site of sphingolipid biosynthesis. ER stress (ER dysfunction) participates in the development of mitochondrial dysfunction during aging. Mitochondria are in close contact with the ER through shared mitochondria associated membranes (MAM). Alteration of sphingolipids contributes to mitochondria-driven cell injury. Cardiolipin is a phospholipid that is critical to maintain enzyme activity in the electron transport chain. The aim of the current study was to characterize the changes in sphingolipids and cardiolipin in ER, MAM, and mitochondria during the progression of aging in young (3 mo.), middle (18 mo.), and aged (24 mo.) C57Bl/6 mouse hearts. ER stress increased in hearts from 18 mo. mice and mice exhibited mitochondrial dysfunction by 24 mo. Hearts were pooled to isolate ER, MAM, and subsarcolemmal mitochondria (SSM). LC-MS/MS quantification of lipid content showed that aging increased ceramide content in ER and MAM. In addition, the contents of sphingomyelin and monohexosylceramides are also increased in the ER from aged mice. Aging increased the total cardiolipin content in the ER. Aging did not alter the total cardiolipin content in mitochondria or MAM yet altered the composition of cardiolipin with aging in line with increased oxidative stress compared to young mice. These results indicate that alteration of sphingolipids can contribute to the ER stress and mitochondrial dysfunction that occurs during aging.
Topics: Animals; Mice; Aging; Endoplasmic Reticulum Stress; Mitochondria; Cardiolipins; Ceramides; Endoplasmic Reticulum; Sphingolipids
PubMed: 37473835
DOI: 10.1016/j.bbalip.2023.159366 -
Ageing Research Reviews Nov 2023Sarcopenia is the accelerated loss of muscle mass, strength and function. Mitochondrial dysfunction was related to the progression of sarcopenia; meanwhile, microRNAs... (Review)
Review
BACKGROUND
Sarcopenia is the accelerated loss of muscle mass, strength and function. Mitochondrial dysfunction was related to the progression of sarcopenia; meanwhile, microRNAs were regarded as core roles in regulating mitochondrial function. Physical exercise is a well-accepted approach to attenuate sarcopenia, yet very few studies depict the molecular mechanisms. The aim of this systematic review is to explore the potential relationships among physical exercise, mitochondrial function, and microRNAs, which may give new insight for retarding sarcopenia.
METHODS
A systematic literature search was performed in PubMed, Embase and Web of Science. The keywords were combined as "(microRNA OR miR) AND mitochondri* AND muscle AND exercise" and searched in all fields. PRISMA guidelines were followed. Information was extracted from the included studies for review.
RESULTS
In this review, 18 preclinical studies and 5 clinical studies were included. Most of the included studies suggested that effective physical exercise had positive effects on mitochondrial functions by regulating microRNAs. The results showed that 12 microRNAs improved mitochondrial functions, while 18 microRNAs suppressed them. Meanwhile, the results showed that 5 microRNAs improved muscle performance.
CONCLUSIONS
This systematic review provides an up-to-date sequential overview and highlights the potential relationship among exercise, mitochondrial function, and microRNAs in muscle. Meanwhile, evidence revealed that physical exercise can improve muscle performance by up-regulating mitochondrial functions, especially mitochondrial biogenesis, through modulating microRNAs.
Topics: Humans; MicroRNAs; Sarcopenia; Muscle, Skeletal; Exercise; Mitochondria; Muscle Strength
PubMed: 37652311
DOI: 10.1016/j.arr.2023.102048 -
Translational Neurodegeneration Apr 2024Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely... (Review)
Review
Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.
Topics: Humans; Mitochondria; Mitochondrial Diseases; Brain; Nervous System Diseases; Biology
PubMed: 38632601
DOI: 10.1186/s40035-024-00409-w -
Molecular Neurobiology Apr 2024The morbidity rate of ischemic stroke is increasing annually with the growing aging population in China. Astrocytes are ubiquitous glial cells in the brain and play a... (Review)
Review
The morbidity rate of ischemic stroke is increasing annually with the growing aging population in China. Astrocytes are ubiquitous glial cells in the brain and play a crucial role in supporting neuronal function and metabolism. Increasing evidence shows that the impairment or loss of astrocytes contributes to neuronal dysfunction during cerebral ischemic injury. The mitochondrion is increasingly recognized as a key player in regulating astrocyte function. Changes in astrocytic mitochondrial function appear to be closely linked to the homeostasis imbalance defects in glutamate metabolism, Ca regulation, fatty acid metabolism, reactive oxygen species, inflammation, and copper regulation. Here, we discuss the role of astrocytic mitochondria in the pathogenesis of brain ischemic injury and their potential as a therapeutic target.
Topics: Humans; Aged; Astrocytes; Brain Ischemia; Brain; Brain Injuries; Mitochondria
PubMed: 37870679
DOI: 10.1007/s12035-023-03714-z -
Nature Cell Biology May 2024Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its... (Review)
Review
Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.
Topics: Mitochondria; Humans; Animals; Energy Metabolism; Adaptation, Physiological; Adenosine Triphosphate; Cell Differentiation
PubMed: 38755301
DOI: 10.1038/s41556-024-01410-1 -
Experimental & Molecular Medicine Feb 2024Mitochondria have been primarily considered intracellular organelles that are responsible for generating energy for cell survival. However, accumulating evidence... (Review)
Review
Mitochondria have been primarily considered intracellular organelles that are responsible for generating energy for cell survival. However, accumulating evidence suggests that mitochondria are secreted into the extracellular space under physiological and pathological conditions, and these secreted mitochondria play diverse roles by regulating metabolism, the immune response, or the differentiation/maturation in target cells. Furthermore, increasing amount of research shows the therapeutic effects of local or systemic administration of mitochondria in various disease models. These findings have led to growing interest in exploring mitochondria as potential therapeutic agents. Here, we discuss the emerging roles of mitochondria as extracellularly secreted organelles to shed light on their functions beyond energy production. Additionally, we provide information on therapeutic outcomes of mitochondrial transplantation in animal models of diseases and an update on ongoing clinical trials, underscoring the potential of using mitochondria as a novel therapeutic intervention.
Topics: Animals; Mitochondria; Cell Communication; Cell Differentiation; Extracellular Space
PubMed: 38172601
DOI: 10.1038/s12276-023-01141-7 -
Journal of Theoretical Biology Sep 2023Mitochondria are the central hub of ATP production in most eukaryotic cells. Cellular power (energy per unit time), which is primarily generated in these organelles, is...
Mitochondria are the central hub of ATP production in most eukaryotic cells. Cellular power (energy per unit time), which is primarily generated in these organelles, is crucial to our understanding of cell function in health and disease. We investigated the relation between a mitochondrion's power (metabolic rate) and host cell size by combining metabolic theory with the analysis of two recent databases, one covering 109 protists and the other 63 species including protists, metazoans, microalgae, and vascular plants. We uncovered an interesting statistical regularity: in well-fed protists, relatively elevated values of mitochondrion power cluster around the smallest cell sizes and the medium-large cell sizes. In contrast, in starved protists and metazoans, the relation between mitochondrion power and cell size is inconclusive, and in microalgae and plants, mitochondrion power seems to increase from smaller cells to larger ones (where this investigation includes plant cells of volume up to ca. 2.18 × 10 μm). Using these results, estimates are provided of the number of active ATP synthase molecules and basal uncouplers.
Topics: Mitochondria; Eukaryota; Organelles; Eukaryotic Cells; Adenosine Triphosphate
PubMed: 37369290
DOI: 10.1016/j.jtbi.2023.111565 -
Mitochondrion May 2024Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life... (Review)
Review
Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.
Topics: Humans; Aging; Potassium Channels; Mitochondria; Animals
PubMed: 38403095
DOI: 10.1016/j.mito.2024.101857