In a 2018 paper and a subsequent article published in 2023, researchers reported that mitochondria maintain temperatures 10-15 degrees celsius higher than the surrounding cytoplasm - a finding that deviates by 5 to 6 orders of magnitude from theoretical predictions based on Fourier's law of heat conduction. In 2022, we proposed a solution to this apparent paradox. In the present perspective, we build upon that framework and introduce new ideas to further unravel how a biological membrane - whether of an organelle or a whole cell - can become significantly warmer than its environment. We propose that proteins embedded in the inner mitochondrial membrane (IMM) can be modeled as ratchet engines, introducing a novel, previously overlooked mode of heat transfer. This mechanism, coupled with localized heat release during the cyclical dehydration-translocation-hydration of ions through membrane proteins, may generate transient but substantial temperature spikes. The cumulative effect of these microscopic events across the three-dimensional surface of the IMM can account for the elevated temperatures detected by molecular probes.
Mitochondrial research is important to ageing, apoptosis, and mitochondrial diseases. In previous works, mitochondria are usually stimulated indirectly by proapoptotic drugs to study mitochondrial development, which is in lack of controllability, or spatial and temporal resolution. These chemicals or even gene techniques regulating mitochondrial dynamics may also activate other inter- or intra-cellular processes simultaneously. Here we demonstrate a photostimulation method on single-mitochondrion level by tightly-focused femtosecond laser that can precisely activate restorable fragmentation of mitochondria which soon recover their original tubular structure after tens of seconds. In this process, series of mitochondrial reactive oxygen species (mROS) flashes are observed and found very critical to mitochondrial fragmentation. Meanwhile, transient openings of mitochondrial permeability transition pores (mPTP), suggested by oscillations of mitochondrial membrane potential, contribute to the scavenging of redundant mROS and recovery of fragmented mitochondria. Those results demonstrate photostimulation as an active, precise and controllable method for the study of mitochondrial oxidat
Experiments by Chretien and co-workers suggest that mitochondria are 10oC hotter than their surroundings. Steady-state theoretical estimates place this difference at a maximum of 10^-5 oC. This million-fold disagreement may be called the hot mitochondrion paradox. It is suggested that every proton translocated via ATP synthase sparks a picosecond temperature-difference spike of the order of magnitude measured by Chretien et al. Time-averaging of these spikes recovers the theoretical value. Further, a temporal and spatial superposition of the fluorescence intensity of a very large number of molecular thermometer molecules in the sample can give the appearance of a steady signal. The inner mitochondrial membrane appears to be flanked by temperature differences fluctuating in time and along the membrane s surface, with hot and cold spots as ultrashort temperature spikes.
The mitochondrion is an important sub-cellular organelle responsible for the cellular energetic source and processes. Owing to its unique sensitivity to heat and reactive oxygen species, the mitochondrion is an appropriate target for photothermal and photodynamic treatment for cancer. However, targeted delivery of therapeutics to mitochondria remains a great challenge due to their location in the sub-cellular compartment and complexity of the intracellular environment. Herein, we report a class of the mitochondrion-targeted liposomal delivery platform consisting of a guanidinium-based dendritic peptide moiety mimicking mitochondrion protein transmembrane signaling to exert mitochondrion-targeted delivery with pH sensitive and charge-reversible functions to enhance tumor accumulation and cell penetration. Compared to the current triphenylphosphonium (TPP)-based mitochondrion targeting system, this dendritic lipopeptide (DLP) liposomal delivery platform exhibits about 3.7-fold higher mitochondrion-targeted delivery efficacy. Complete tumor eradication is demonstrated in mice bearing 4T1 mammary tumors after combined photothermal and photodynamic therapies delivered by the reported DLP platform.
The mitochondrion of Plasmodium species is a validated drug target. However, very little is known about the functions of this organelle. In this review, we utilize data available from the Plasmodium falciparum genome sequencing project to piece together putative metabolic pathways that occur in the parasite, comparing this with the existing biochemical and cell biological knowledge. The Plasmodium mitochondrion contains both conserved and unusual features, including an active electron transport chain and many of the necessary enzymes for coenzyme Q and iron-sulphur cluster biosynthesis. It also plays an important role in pyrimidine metabolism. The mitochondrion participates in an unusual hybrid haem biosynthesis pathway, with enzymes localizing in both the mitochondrion and plastid organelles. The function of the tricarboxylic acid cycle in the mitochondrion is unclear. We discuss directions for future research into this fascinating, yet enigmatic, organelle.
Adenosine triphosphate (ATP) is mainly produced in the mitochondrion and used as a universal energy source for various cellular events. Various fluorescent probes for ATP have been established successfully, but most of them are not appropriate for monitoring the fluctuation of the mitochondrial ATP level. Herein, a fluorescent probe named Mito-Rh is first synthesized and used to recognize ATP in mitochondrion. In the probe, rhodamine, diethylenetriamine, and triphenylphosphonium are selected as fluorophore, reaction site, and mitochondrion-targeting group, respectively. Probe Mito-Rh shows high sensitivity to ATP with 81-fold fluorescence enhancement, and the detection range (0.1-10 mM) can match the concentration level of ATP in the mitochondrion. Moreover, Mito-Rh provides excellent selectivity toward ATP over other biological anions (ADP, AMP, GTP, CTP, UTP) owing to a concurrent effect of dual recognition sites (hydrogen bond and π-π stacking). In particular, the probe can localize in mitochondrion specifically and demonstrates utility in the real-time detection of mitochondrial ATP concentration changes.
The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell iron-processing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial iron-processing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.
The discovery of mitochondrion-type genes in organisms thought to lack mitochondria led to the demonstration that hydrogenosomes share a common ancestry with mitochondria, as well as the discovery of mitosomes in multiple eukaryotic lineages. No examples of examined eukaryotes lacking a mitochondrion-related organelle exist, implying that the endosymbiont that gave rise to the mitochondrion was present in the first eukaryote. These organelles, known as hydrogenosomes, mitosomes, or mitochondrion-like organelles, are typically reduced, both structurally and biochemically, relative to classical mitochondria. However, despite their diversification and adaptation to different niches, all appear to play a role in Fe-S cluster assembly, as observed for mitochondria. Although evidence supports the use of common protein targeting mechanisms in the biogenesis of these diverse organelles, divergent features are also apparent. This review examines the metabolism and biogenesis of these organelles in divergent unicellular microbes, with a focus on parasitic protists.
The kinetoplast DNA (kDNA) is the archetype of a two-dimensional Olympic network, composed of thousands of DNA minicircles and found in the mitochondrion of certain parasites. The evolution, replication and self-assembly of this structure are fascinating open questions in biology that can also inform us how to realise synthetic Olympic networks in vitro. To obtain a deeper understanding of the structure and assembly of kDNA networks, we sequenced the Crithidia fasciculata kDNA genome and performed high-resolution Atomic Force Microscopy (AFM) and analysis of kDNA networks that had been partially digested by selected restriction enzymes. We discovered that these topological perturbations lead to networks with significantly different geometrical features and morphologies with respect to the unperturbed kDNA, and that these changes are strongly dependent on the class of DNA circles targeted by the restriction enzymes. Specifically, cleaving maxicircles leads to a dramatic reduction in network size once adsorbed onto the surface, whilst cleaving both maxicircles and a minor class of minicircles yields non-circular and deformed structures. We argue that our results are a consequence of
The origin of organelles (mitochondrion, chloroplast and nucleus) remains enigmatic. The endosymbiotic hypothesis that chloroplasts, mitochondria and nuclei descend from the endosymbiotic cyanobacterium, bacterium and archaebacterium respectively is dominant yet uncompelling, while our discovery of de novo organelle biogenesis in the cyanobacterium TDX16 that had acquired the genome of its green algal host Haematococcus pluvialis disproves this hypothesis. In light of organelle biogenesis in the cyanobacterium TDX16 in combination with the relevant cellular and molecular evidence, we propose genome hybridization hypothesis (GHH) that the origin of organelles and origin of eukaryotes as well as the diversification of organelles and speciation of eukaryotes are unified and achieved by genome hybridization: the endosymbiotic cyanobacteria/bacteria obtain the genomes of their archaebacterial or eukaryotic hosts and hybridize with their own ones resulting in expanded genomes containing a mixture of hybrid prokaryotic genes and eukaryotic genes, and thus have to compartmentalize to accommodate different genes for specialized function of photosynthesis (chloroplast), respiration (mitochon
A production of heat by mitochondria is critical for maintaining body temperature, regulating metabolic rate and preventing oxidative damage to mitochondria and cells. Up to now mitochondrion heat production was characterized only by methods based on fluorescent probes which are sensitive to environmental variations (viscosity, pH, ionic strength, quenching etc.). Herein, for the first time the heat release of isolated mitochondria was unambiguously measured by a diamond thermometer (DT) which is absolutely indifferent to external non-thermal parameters. We show that during total uncoupling of transmembrane potential by CCCP application the temperature near mitochondria rises by 4-22 °C above the ambient temperature, with an absolute maximum of 45 °C. Such a broad temperature response may be associated with the heterogeneity of the mitochondria themselves as well as their aggregations in the isolated suspension. It also revealed spontaneous temperature bursts prior to CCCP application that can reflect involvement of some mitochondria to ATP synthesis or membrane potential leaking to avoid reactive oxygen species hyperproduction. The used temperature sensor and the data obtained she
Mitochondria in plant cells form strikingly dynamic populations of largely individual organelles. Each mitochondrion contains on average less than a full copy of the mitochondrial DNA (mtDNA) genome. Here, we asked whether mitochondrial dynamics may allow individual mitochondria to `collect' a full copy of the mtDNA genome over time, by facilitating exchange between individuals. Akin to trade on a social network, exchange of mtDNA fragments across organelles may lead to the emergence of full `effective' genomes in individuals over time. We characterise the collective dynamics of mitochondria in \emph{Arabidopsis thaliana} hypocotyl cells using a recent approach combining single-cell timelapse microscopy, video analysis, and network science. We then use a quantitative model to predict the capacity for the sharing and accumulation of genetic information through the networks of encounters between mitochondria. We find that biological encounter networks are strikingly well predisposed to support the collection of full genomes over time, outperforming a range of other networks generated from theory and simulation. Using results from the coupon collector's problem, we show that the upper
We studied a relations between the triplet frequency composition of mitochondria genomes, and the phylogeny of their bearers. First, the clusters in 63dimensional space were developed due to $K$-means. Second, the clade composition of those clusters has been studied. It was found that genomes are distributed among the clusters very regularly, with strong correlation to taxonomy. Strong co-evolution manifests through this correlation: the proximity in frequency space was determined over the mitochondrion genomes, while the proximity in taxonomy was determined morphologically.
The exploration of the structural topology and the organizing principles of genome-based large-scale metabolic networks is essential for studying possible relations between structure and functionality of metabolic networks. Topological analysis of graph models has often been applied to study the structural characteristics of complex metabolic networks.In this work, metabolic networks of 75 organisms were investigated from a topological point of view. Network decomposition of three microbes (Escherichia coli, Aeropyrum pernix and Saccharomyces cerevisiae) shows that almost all of the sub-networks exhibit a highly modularized bow-tie topological pattern similar to that of the global metabolic networks. Moreover, these small bow-ties are hierarchically nested into larger ones and collectively integrated into a large metabolic network, and important features of this modularity are not observed in the random shuffled network. In addition, such a bow-tie pattern appears to be present in certain chemically isolated functional modules and spatially separated modules including carbohydrate metabolism, cytosol and mitochondrion respectively. The highly modularized bow-tie pattern is present
Shuttle-assisted charge transfer is pivotal for the efficient energy transduction from the food-stuff electrons to protons in the respiratory chain of animal cells and bacteria. The respiratory chain consists of four metalloprotein Complexes (I-IV) embedded in the inner membrane of a mitochondrion. Three of these complexes pump protons across the membrane, fuelled by the energy of food-stuff electrons. Despite extensive biochemical and biophysical studies, the physical mechanism of this proton pumping is still not well understood. Here we present a nanoelectromechanical model of the electron-driven proton pump related to the second loop of the respiratory chain, where a lipid-soluble ubiquinone molecule shuttles between the Complex I and Complex III, carrying two electrons and two protons. We show that the energy of electrons can be converted to the transmembrane proton potential gradient via the electrostatic interaction between electrons and protons on the shuttle. We find that the system can operate either as a proton pump, or, in the reverse regime, as an electron pump. For membranes with various viscosities, we demonstrate that the uphill proton current peaks near the body tem
[abridged] Background: The distribution of chemical species in an open system at metastable equilibrium can be expressed as a function of environmental variables which can include temperature, oxidation-reduction potential and others. Calculations of metastable equilibrium for various model systems were used to characterize chemical transformations among proteins and groups of proteins found in different compartments of yeast cells. Results: With increasing oxygen fugacity, the relative metastability fields of model proteins for major subcellular compartments go as mitochondrion, endoplasmic reticulum, cytoplasm, nucleus. In a metastable equilibrium setting at relatively high oxygen fugacity, proteins making up actin are predominant, but those constituting the microtubule occur with a low chemical activity. A reaction sequence involving the microtubule and spindle pole proteins was predicted by combining the known intercompartmental interactions with a hypothetical program of oxygen fugacity changes in the local environment. In further calculations, the most-abundant proteins within compartments generally occur in relative abundances that only weakly correspond to a metastable equi
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NASA’s Fermi telescope has detected what may be the first confirmed gamma-ray signal from a superluminous supernova — one of the most extreme explosions in the universe。 Scientists believe the blast was powered by a rapidly spinning magnetar, an exotic neutron star with unbelievably strong magnetic fields。 The event, called SN 2017egm, erupted 440