Mitochondrial DNA depletion syndrome (MDS) is a group of severe inherited disorders caused by mutations in genes, such as deoxyribonucleoside kinase (DGUOK). A great majority of DGUOK mutant MDS ...patients develop iron overload progressing to severe liver failure. However, the pathological mechanisms connecting iron overload and hepatic damage remains uncovered. Here, two patients’ skin fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs) and then corrected by CRISPR/Cas9. Patient‐specific iPSCs and corrected iPSCs‐derived high purity hepatocyte organoids (iHep‐Orgs) and hepatocyte‐like cells (iHep) are generated as cellular models for studying hepatic pathology. DGUOK mutant iHep and iHep‐Orgs, but not control and corrected one, are more sensitive to iron overload‐induced ferroptosis, which can be rescued by N‐Acetylcysteine (NAC). Mechanically, this ferroptosis is a process mediated by nuclear receptor co‐activator 4 (NCOA4)‐dependent degradation of ferritin in lysosome and cellular labile iron release. This study reveals the underlying pathological mechanisms and the viable therapeutic strategies of this syndrome, and is the first pure iHep‐Orgs model in hereditary liver diseases.
Iron overload is an important feature in deoxyribonucleoside kinase mutant mitochondrial DNA depletion syndrome. A combined model of patient‐specific induced pluripotent stem cells‐derived liver organoids and hepatocytes reveals a sensitivity to iron overload‐induced ferroptosis in patients. This ferroptosis is a process by NCOA4‐dependent degradation of ferritin in lysosome and cellular labile iron release.
Induced pluripotent stem cells (iPSCs) have fewer and immature mitochondria than somatic cells and mainly rely on glycolysis for energy source. During somatic cell reprogramming, somatic mitochondria ...and other organelles get remodeled. However, events of organelle remodeling and interaction during somatic cell reprogramming have not been extensively explored. We show that both SKP/SKO (Sox2, Klf4, Pou5f1/Oct4) and SKPM/SKOM (SKP/SKO plus Myc/c-Myc) reprogramming lead to decreased mitochondrial mass but with different kinetics and by divergent pathways. Rapid, MYC/c-MYC-induced cell proliferation may function as the main driver of mitochondrial decrease in SKPM/SKOM reprogramming. In SKP/SKO reprogramming, however, mitochondrial mass initially increases and subsequently decreases via mitophagy. This mitophagy is dependent on the mitochondrial outer membrane receptor BNIP3L/NIX but not on mitochondrial membrane potential (ΔΨ
m
) dissipation, and this SKP/SKO-induced mitophagy functions in an important role during the reprogramming process. Furthermore, endosome-related RAB5 is involved in mitophagosome formation in SKP/SKO reprogramming. These results reveal a novel role of mitophagy in reprogramming that entails the interaction between mitochondria, macroautophagy/autophagy and endosomes.
Maintaining a healthy and functional mitochondrial network is crucial for cell survival and function. Protein misfolding and dysfunction are particularly prevalent in them due to physiological ...adaptations and stress conditions. For mitochondria to function properly, multiple quality control systems have evolved to ensure that there are enough mitochondria to meet cells’ needs, damaged mitochondrial proteins or mitochondrial parts can be eliminated using these pathways. Several mechanisms control mitochondrial quality, including protein, organelle, and cellular levels. As the extensive study of canonical mitochondrial quality‐mitophagy, this paper reviews the processes and mechanisms of mitochondrial quality control independent of autophagy, including mitochondrial protein and DNA degradation, mitochondria‐derived vesicles and mitochondria‐derived compartments, mitochondrial secretion, tunneling nanotubes, mitocytosis, and mitolysosome exocytosis. Understanding these novel quality control pathways may provide insights into mitochondrial homeostasis and for developing targeted treatments for diseases where these systems fail.
Maintaining a healthy and functional mitochondrial network is crucial for cell survival and function. Related studies have confirmed that mitochondrial autophagy (mitophagy) can clean damaged mitochondria for quality control. We review here the processes involved in autophagy‐independent mitochondrial quality control, which may provide a direction for developing targeted treatments for diseases where these systems fail.
Quality control of mitochondria is essential for their homeostasis and function. Light chain 3 (LC3) associated autophagosomes-mediated mitophagy represents a canonical mitochondrial quality control ...pathway. Alternative quality control processes, such as mitochondrial-derived vesicles (MDVs), have been discovered, but the intact mitochondrial quality control remains unknown. We recently discovered a novel mitolysosome exocytosis mechanism for mitochondrial quality control in flunarizine (FNZ)-induced mitochondria clearance, where autophagosomes are not required, but rather mitochondria are engulfed directly by lysosomes, mediating mitochondrial secretion. As FNZ results in parkinsonism, we propose that excessive mitolysosome exocytosis is the cause.
The lack of highly efficient catalysts severely hinders large‐scale application of electrochemical hydrogen evolution reaction (HER) for hydrogen production from water. Herein, synergistic cascade ...hydrogen evolution boosting by combining the strategies of carbon layer confinement and surface oxophilicity modification is realized. The carbon layers confined ultrafine RuCr nanoparticles (RuCr@C) exhibit outstanding HER activity (j10 = 19 mV, turnover frequency = 4.25 H2 s‐1), surpassing the benchmark Pt/C and most of the reported HER catalysts. Combined experimental verifications and theoretical simulations reveal that surface adsorption modification and electronic structure regulation synergistically boosts the HER kinetics over the RuCr@C catalyst. The Volmer step is accelerated by stabilizing the final state of water dissociation (*H and *OH) through Cr doping, and the Heyrovsky step is promoted via carbon layers confinement. As such, this work highlights a synergistic cascade strategy to boost HER kinetics which is of fundamental importance to accelerate future advances in electrocatalysis.
A synergistic cascade strategy is employed to boost hydrogen evolution via combining carbon layer confinement and surface oxophilicity modification. The as crafted RuCr nanoparticles confined in carbon layers exhibit outstanding hydrogen evolution reaction (HER) activity (j10 = 19 mV, turnover frequency = 4.25 H2 s−1), surpassing the benchmark Pt/C and most of the reported HER catalysts.
Heteroplasmic cells, harboring both mutant and normal mitochondrial DNAs (mtDNAs), must accumulate mutations to a threshold level before respiratory activity is affected. This phenomenon has led to ...the hypothesis of mtDNA complementation by inter-mitochondrial content mixing. The precise mechanisms of heteroplasmic complementation are unknown, but it depends both on the mtDNA nucleoid dynamics among mitochondria as well as the mitochondrial dynamics as influenced by mtDNA. We tracked nucleoids among the mitochondria in real time to show that they are shared after complete fusion but not ‘kiss-and-run’. Employing a cell hybrid model, we further show that mtDNA-less mitochondria, which have little ATP production and extensive Opa1 proteolytic cleavage, exhibit weak fusion activity among themselves, yet remain competent in fusing with healthy mitochondria in a mitofusin- and OPA1-dependent manner, resulting in restoration of metabolic function. Depletion of mtDNA by overexpression of the matrix-targeted nuclease UL12.5 resulted in heterogeneous mitochondrial membrane potential (ΔΨm) at the organelle level in mitofusin-null cells but not in wild type. In this system, overexpression of mitofusins or application of the fusion-promoting drug M1 could partially rescue the metabolic damage caused by UL12.5. Interestingly, mtDNA transcription/translation is not required for normal mitochondria to restore metabolic function to mtDNA-less mitochondria by fusion. Thus, interplay between mtDNA and fusion capacity governs a novel ‘initial metabolic complementation’.
Selective elimination of mitochondria by autophagy is a critical strategy for a variety of physiological processes, including development, cell-fate determination and stress response. Although ...several mechanisms have been identified as responsible for selective degradation of mitochondria, such as the PINK1-PRKN/PARKIN- and receptor-dependent pathways, aspects of the mechanisms and particularly the principles underlying the selection process of mitochondria remain obscure. Here, we addressed a new selection strategy in which the selective elimination of mitochondria is dependent on organellar topology. We found that populations of mitochondria undergo different topological transformations under serum starvation, either swelling or forming donut shapes. Swollen mitochondria are associated with mitochondrial membrane potential dissipation and PRKN recruitment, which promote their selective elimination, while the donut topology maintains mitochondrial membrane potential and helps mitochondria resist autophagy. Mechanistic studies show that donuts resist autophagy even after depolarization through preventing recruitment of autophagosome receptors CALCOCO2/NDP52 and OPTN even after PRKN recruitment. Our results demonstrate topology-dependent, bifurcated mitochondrial recycling under starvation, that is swollen mitochondria undergo removal by autophagy, while donut mitochondria undergo fission and fusion cycles for reintegration. This study reveals a novel morphological selection for control of mitochondrial quality and quantity under starvation.
The mitochondrial genome transcribes 13 mRNAs coding for well-known proteins essential for oxidative phosphorylation. We demonstrate here that cytochrome b (CYTB), the only mitochondrial-DNA-encoded ...transcript among complex III, also encodes an unrecognized 187-amino-acid-long protein, CYTB-187AA, using the standard genetic code of cytosolic ribosomes rather than the mitochondrial genetic code. After validating the existence of this mtDNA-encoded protein arising from cytosolic translation (mPACT) using mass spectrometry and antibodies, we show that CYTB-187AA is mainly localized in the mitochondrial matrix and promotes the pluripotent state in primed-to-naive transition by interacting with solute carrier family 25 member 3 (SLC25A3) to modulate ATP production. We further generated a transgenic knockin mouse model of CYTB-187AA silencing and found that reduction of CYTB-187AA impairs females’ fertility by decreasing the number of ovarian follicles. For the first time, we uncovered the novel mPACT pattern of a mitochondrial mRNA and demonstrated the physiological function of this 14th protein encoded by mtDNA.
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•CYTB encodes a new protein, CYTB-187AA, using the standard genetic code in cytosol•CYTB-187AA promotes the pluripotent state in primed-to-naive transition•CYTB-187AA interacts with SLC25A3 to modulate ATP production•CYTB-187AA regulates the fertility of female mice via ovarian follicles
We discovered a dual translation pattern of the mitochondrial-encoded gene CYTB whereby, in addition to producing CYTB in complex III, CYTB also encodes a new mitochondrial protein, CYTB-187AA, which is translated by cytosolic ribosomes using the standard genetic code and modulates mammalian early development.
Reprogramming of somatic cells to induced pluripotent stem cells reconfigures chromatin modifications. Whether and how this process is regulated by signals originating in the mitochondria remain ...unknown. Here we show that the mitochondrial permeability transition pore (mPTP), a key regulator of mitochondrial homeostasis, undergoes short-term opening during the early phase of reprogramming and that this transient activation enhances reprogramming. In mouse embryonic fibroblasts, greater mPTP opening correlates with higher reprogramming efficiency. The reprogramming-promoting function of mPTP opening is mediated by plant homeodomain finger protein 8 (PHF8) demethylation of H3K9me2 and H3K27me3, leading to reduction in their occupancies at the promoter regions of pluripotency genes. mPTP opening increases PHF8 protein levels downstream of mitochondrial reactive oxygen species production and miR-101c and simultaneously elevates levels of PHF8's cofactor, α-ketoglutarate. Our findings represent a novel mitochondria-to-nucleus pathway in cell fate determination by mPTP-mediated epigenetic regulation.
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•mPTP exhibits short-term opening during the early phase of reprogramming•Early-phase mPTP opening enhances reprogramming•mPTP opening decreases H3K9me2/H3K27me3 methylation, mediated by PHF8•PHF8 activity is enhanced via mitochondrial ROS and miR-101c
Ying et al. show that transient activation of the mitochondrial permeability transition pore (mPTP) is involved in the early phase of somatic cell reprogramming to induced pluripotent stem cells. Short-term mPTP opening triggers a mitochondrial ROS/miR-101c pathway that enhances PHF8-mediated H3K9me2/H3K27me3 demethylation of pluripotency genes.
Optic Atrophy 1 (OPA1), a mitochondrial inner protein, is involved in both mitochondrial fusion dynamic and cell apoptosis. OPA1 Exon4b (OPA1-Exon4b) was reported to be downregulated in ...hepatocellular carcinoma (HCC). However, the relationship between OPA1-Exon4b and HCC remains unclear. Here we demonstrated that OPA1-Exon4b is related with migration using genome-wide transcriptome profiling. OPA1-Exon4b overexpression suppresses the migration and invasion, and cellular ATP production in HCC cells. The inhibition of migration and invasion by OPA1-Exon4b overexpression could be rescued by ATP addition, showing that OPA1-Exon4b suppresses the migration and invasion by decreasing ATP. We further demonstrated OPA1 overexpression induces the enlargement of mtDNA nucleoids in HCC cells. Thus, our study demonstrated a key role of OPA1-Exon4b to regulate the migration and invasion in HCC, which could provide a new prospect for the clinical diagnosis and therapy of HCC.
•OPA1-Exon4b relates with migration.•OPA1-Exon4b OE suppresses migration and invasion.•OPA1-Exon4b on migration and invasion is dependent on ATP.•OPA1 OE induces mtDNA nucleoids enlargement.
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