Subscribe to the gold package and get unlimited access to Shamra Academy
Register a new userMitochondrial heterogeneity
135
0
0.0
(
0
)
Ask ChatGPT about the research
No Arabic abstract
Cell-to-cell heterogeneity drives a range of (patho)physiologically important phenomena, such as cell fate and chemotherapeutic resistance. The role of metabolism, and particularly mitochondria, is increasingly being recognised as an important explanatory factor in cell-to-cell heterogeneity. Most eukaryotic cells possess a population of mitochondria, in the sense that mitochondrial DNA (mtDNA) is held in multiple copies per cell, where the sequence of each molecule can vary. Hence intra-cellular mitochondrial heterogeneity is possible, which can induce inter-cellular mitochondrial heterogeneity, and may drive aspects of cellular noise. In this review, we discuss sources of mitochondrial heterogeneity (variations between mitochondria in the same cell, and mitochondrial variations between supposedly identical cells) from both genetic and non-genetic perspectives, and mitochondrial genotype-phenotype links. We discuss the apparent homeostasis of mtDNA copy number, the observation of pervasive intra-cellular mtDNA mutation (we term `microheteroplasmy) and developments in the understanding of inter-cellular mtDNA mutation (`macroheteroplasmy). We point to the relationship between mitochondrial supercomplexes, cristal structure, pH and cardiolipin as a potential amplifier of the mitochondrial genotype-phenotype link. We also discuss mitochondrial membrane potential and networks as sources of mitochondrial heterogeneity, and their influence upon the mitochondrial genome. Finally, we revisit the idea of mitochondrial complementation as a means of dampening mitochondrial genotype-phenotype links in light of recent experimental developments. The diverse sources of mitochondrial heterogeneity, as well as their increasingly recognised role in contributing to cellular heterogeneity, highlights the need for future single-cell mitochondrial measurements in the context of cellular noise studies.
rate research
Read More
Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.
The proper functioning of mitochondria requires that both the mitochondrial and the nuclear genome are functional. To investigate the importance of the mitochondrial genome, which encodes only 13 subunits of the respiratory complexes, the mitochondrial rRNAs and a few tRNAs, we performed a comparative study on the 143B cell line and on its Rho-0 counterpart, i.e., devoid of mitochondrial DNA. Quantitative differences were found, of course in the respiratory complexes subunits, but also in the mitochondrial translation apparatus, mainly mitochondrial ribosomal proteins, and in the ion and protein import system, i.e., including membrane proteins. Various mitochondrial metabolic processes were also altered, especially electron transfer proteins and some dehydrogenases, but quite often on a few proteins for each pathway. This study also showed variations in some hypothetical or poorly characterized proteins, suggesting a mitochondrial localization for these proteins. Examples include a stomatin-like protein and a protein sharing homologies with bacterial proteins implicated in tyrosine catabolism. Proteins involved in apoptosis control are also found modulated in Rho-0 mitochondria.
Muscle uses Ca2+ as a messenger to control contraction and relies on ATP to maintain the intracellular Ca2+ homeostasis. Mitochondria are the major sub-cellular organelle of ATP production. With a negative inner membrane potential, mitochondria take up Ca2+ from their surroundings, a process called mitochondrial Ca2+ uptake. Under physiological conditions, Ca2+ uptake into mitochondria promotes ATP production. Excessive uptake causes mitochondrial Ca2+ overload, which activates downstream adverse responses leading to cell dysfunction. Moreover, mitochondrial Ca2+ uptake could shape spatio-temporal patterns of intracellular Ca2+ signaling. Malfunction of mitochondrial Ca2+ uptake is implicated in muscle degeneration. Unlike non-excitable cells, mitochondria in muscle cells experience dramatic changes of intracellular Ca2+ levels. Besides the sudden elevation of Ca2+ level induced by action potentials, Ca2+ transients in muscle cells can be as short as a few milliseconds during a single twitch or as long as minutes during tetanic contraction, which raises the question whether mitochondrial Ca2+ uptake is fast and big enough to shape intracellular Ca2+ signaling during excitation-contraction coupling and creates technical challenges for quantification of the dynamic changes of Ca2+ inside mitochondria. This review focuses on characterization of mitochondrial Ca2+ uptake in skeletal muscle and its role in muscle physiology and diseases.
Mounting evidence for the role of oxidative stress in the degeneration of articular cartilage after an injurious impact requires our modeling & simulation efforts to temporarily shift from just describing the effect of mechanical stress and inflammation on osteoarthritis (OA). The hypothesis that the injurious impact causes irreversible damage to chondrocyte mitochondria, which in turn increase their production of free radicals, affecting their energy production and their ability to rebuild the extracellular matrix, has to be modeled and the processes quantified in order to further the understanding of OA, its causes, and viable treatment options. The current article presents a calibrated model that captures the damage oxidative stress incurs on the cell viability, ATP production, and cartilage stability in a cartilage explant after a drop-tower impact. The model validates the biological hypothesis and will be used in further efforts to identify possibilities for treatment and be a part of a bigger modeling & simulation framework for the development of OA.
The expansion of deleted mitochondrial DNA (mtDNA) molecules has been linked to ageing, particularly in skeletal muscle fibres; its mechanism has remained unclear for three decades. Previous accounts assigned a replicative advantage to the deletions, but there is evidence that cells can, instead, selectively remove defective mtDNA. We present a spatial model that, without a replicative advantage, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with wave speed consistent with experimental data, unlike a standard model based on replicative advantage. We provide a formula that predicts that the wave speed drops with copy number, in agreement with experimental data. Crucially, our model yields travelling waves of mutants even if mutants are preferentially eliminated. Justified by this exemplar of how noise, density and spatial structure affect muscle ageing, we introduce the mechanism of stochastic survival of the densest, an alternative to replicative advantage, that may underpin other phenomena, like the evolution of altruism.
Log in to be able to interact and post comments
comments
Fetching comments
Sign in to be able to follow your search criteria
