bims-nenemi 2024-12-15 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2024–12–15
fifteen papers selected by
Marco Tigano, Thomas Jefferson University

Cooperative Role of PACT and ADAR1 in Preventing Aberrant PKR Activation by Self-Derived Double-Stranded RNA.
Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
Modulation of mitochondrial dynamics genes and mtDNA during embryonic development and under UVB exposure.
Reactive oxygen species control protein degradation at the mitochondrial import gate.
Cholesterol restriction primes antiviral innate immunity via SREBP1-driven noncanonical type I IFNs.
Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
Energy metabolism rewiring following acute UVB irradiation is largely dependent on nuclear DNA damage.
Constraint reveals the mitochondrial genome sites most important for health and disease.
Mitochondrial dysfunction of Astrocyte induces cell activation under high salt condition.
Oxidative Injury to Lung Mitochondrial DNA is a Key Contributor for the Development of Chemical Lung Injury.
Urban aerosol particulate matter promotes cellular senescence through mitochondrial ROS-mediated Akt/Nrf2 downregulation in human retinal pigment epithelial cells.
TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach.
Expanded-access use of elamipretide in a critically ill patient with Barth syndrome.
Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake.
Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.

bioRxiv. 2024 Nov 27. pii: 2024.11.27.625712. [Epub ahead of print]

Cooperative Role of PACT and ADAR1 in Preventing Aberrant PKR Activation by Self-Derived Double-Stranded RNA.

Lavanya Manjunath, Gisselle Santiago, Pedro Ortega, Ambrocio Sanchez, Sunwoo Oh, Alexander Garcia, Elodie Bournique, Alexis Bouin, Bert L Semler, Dheva Setiaputra, Rémi Buisson.

Double-stranded RNAs (dsRNAs) produced during viral infections are recognized by the innate immune sensor protein kinase R (PKR), triggering a host translation shutoff that inhibits viral replication and propagation. Given the harmful effects of uncontrolled PKR activation, cells must tightly regulate PKR to ensure that its activation occurs only in response to viral infections, not endogenous dsRNAs. Here, we use CRISPR-Translate, a FACS-based genome-wide CRISPR-Cas9 knockout screening method that exploits translation levels as a readout and identifies PACT as a key inhibitor of PKR during viral infection. We find that cells deficient for PACT hyperactivate PKR in response to several different RNA viruses, raising the question of why cells need to limit PKR activity. Our results demonstrate that PACT cooperates with ADAR1 to suppress PKR activation from self-dsRNAs in uninfected cells. The simultaneous deletion of PACT and ADAR1 results in synthetic lethality, which can be fully rescued in PKR-deficient cells. We propose that both PACT and ADAR1 act as essential barriers against PKR, creating a threshold of tolerable levels to endogenous dsRNA in cells without activating PKR-mediated translation shutdown and cell death.

DOI: https://doi.org/10.1101/2024.11.27.625712
Brain Commun. 2024 ;6(6): fcae404

Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.

Jacques Bureau, Florence Manero, Olivier Baris, Alexia Bodin, Christophe Verny, Arnaud Chevrollier, Guy Lenaers, Philippe Codron.

  Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches.

Keywords:  Leber hereditary optic neuropathy; Opa1; dominant optic atrophy; hereditary optic neuropathy; mitochondria

DOI:  https://doi.org/10.1093/braincomms/fcae404
Comp Biochem Physiol A Mol Integr Physiol. 2024 Dec 09. pii: S1095-6433(24)00217-4. [Epub ahead of print]300 111790

Modulation of mitochondrial dynamics genes and mtDNA during embryonic development and under UVB exposure.

Thaline de Quadros, Michael Lorenz Jaramillo, Cairé Barreto, Rafael Diego da Rosa, Madson Silveira de Melo, Evelise Maria Nazari.

  Studies using the embryos of the freshwater prawn Macrobrachium olfersii have reported changes in embryonic cells after exposure to ultraviolet B (UVB) radiation, such as DNA damage and apoptosis activation. Considering the importance of mitochondria in embryonic cells, this study aimed to characterize the aspects of mitochondrial morphofunctionality in M. olfersii embryos and mitochondrial responses to UVB radiation exposure. The coding sequences of genes Tfam, Nrf1, Mfn1, and Drp1 were identified from the transcriptome of M. olfersii embryos. The phylogenetic relationship showed strong amino acid identity and a highly conserved nature of the sequences. Additionally, the number of mitochondrial DNA (mtDNA) copies were higher in the early embryonic days. The results showed that the expression of the analyzed genes was highly regulated during embryonic development, increasing their levels near hatching. Furthermore, when embryos were exposed to UVB radiation, mitochondrial biogenesis was activated, recognized by higher levels of transcripts of genes Tfam and Nrf1, accompanied by mitochondrial fission. Additionally, these mitochondrial events were supported by an increase of mtDNA copies. Our results showed that UVB radiation was able to change the mitochondrial morphofunctionality, and under the current knowledge, certainly compromise embryonic cellular integrity. Additionally, mitochondria is an important cellular target of this radiation and its responses can be used to assess environmental stress caused by UVB radiation in embryos of aquatic species.

Keywords:  Bioinformatic tool; Embryo; Embryotoxicity; Fusion/fission mitochondrial; Macrobrachium prawn; Ultraviolet radiation

DOI:  https://doi.org/10.1016/j.cbpa.2024.111790
Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00909-2. [Epub ahead of print]84(23): 4612-4628.e13

Reactive oxygen species control protein degradation at the mitochondrial import gate.

Rachael McMinimy, Andrew G Manford, Christine L Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y Shih, Christopher M Rose, John Kuriyan, Baris Bingol, Michael Rapé.

  While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.

Keywords:  FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2024.11.004
EMBO Rep. 2024 Dec 12.

Cholesterol restriction primes antiviral innate immunity via SREBP1-driven noncanonical type I IFNs.

Tasuku Nishimura, Takahisa Kouwaki, Ken Takashima, Akie Ochi, Yohana S Mtali, Hiroyuki Oshiumi.

  Cholesterol metabolism is associated with innate immune responses; however, the underlying mechanism remains unclear. Here, we perform chemical screening to isolate small molecules influencing RIG-I activity, a cytoplasmic viral RNA sensor. We find that statins, which inhibit cholesterol synthesis, dramatically enhance RIG-I-dependent antiviral responses in specific cell types. Since statins exhibit pleiotropic effects on type I interferon (IFN) responses, we further focus on their effects on RIG-I signaling. The restriction of cholesterol synthesis induces expression of noncanonical type I IFNs, such as IFN-ω, in an SREBP1 transcription factor-dependent manner. This pathway subsequently enhances RIG-I-mediated signaling following viral infection. Administration of statins augments RIG-I-dependent cytokine expression in the lungs of mice. Conversely, a mouse obesity model shows a diminished RIG-I response. Single-cell transcriptome analyses reveal a subset of alveolar macrophages that increase RIG-I expression in response to inhibited cholesterol synthesis in vivo. This study reveals SREBP1-mediated noncanonical type I IFN expression, linking cholesterol metabolism and RIG-I signaling.

Keywords:  Cholesterol; Innate Immunity; RIG-I; Type I Interferon; Virus

DOI:  https://doi.org/10.1038/s44319-024-00346-9
Autophagy. 2024 Dec 12. 1-16

Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.

Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen.

  Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A1 or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.Abbreviation: ΔΨm: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.

Keywords:  PI3K-AKT-MTORC1; m.3243A>G; mitochondria; mitophagy; mtDNA mutations; nutrient signaling

DOI:  https://doi.org/10.1080/15548627.2024.2437908
Free Radic Biol Med. 2024 Dec 10. pii: S0891-5849(24)01139-0. [Epub ahead of print]

Energy metabolism rewiring following acute UVB irradiation is largely dependent on nuclear DNA damage.

Léa Dousset, Walid Mahfouf, Hadi Younes, Hala Fatrouni, Corinne Faucheux, Elodie Muzotte, Ferial Khalife, Rodrigue Rossignol, François Moisan, Muriel Cario, Stéphane Claverol, Laure Favot-Laforge, Anni I Nieminen, Seppo Vainio, Nsrein Ali, Hamid-Reza Rezvani.

Solar ultraviolet B (UVB) radiation-induced DNA damage is a well-known initiator of skin carcinomas. The UVB-induced DNA damage response (DDR) involves series of signaling cascades that are activated to maintain cell integrity. Among the different biological processes, little is known about the role of energy metabolism in the DDR. We sought to determine whether UVB-induced nuclear and/or mitochondrial cyclobutane pyrimidine dimers (CPDs) alter cellular energy metabolism. To gain insight into this question, we took advantage of keratinocytes expressing nuclear or mitochondrial CPD photolyase. Applying a quantitative proteomic approach and targeted metabolomics, we observed biphasic alterations in multiple metabolic pathways and in the abundance of various metabolites, largely influenced by the presence of genomic CPDs. The heightened oxygen consumption rate post-irradiation, along with mitochondrial structural rearrangements, was found to be dependent on both mitochondrial and nuclear CPDs. Understanding the influence of nuclear and mitochondrial DNA damage on keratinocyte responses to UVB irradiation deepens current knowledge regarding skin cancer prevention, initiation, and therapy.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.12.030
Nature. 2024 Dec 11.

Constraint reveals the mitochondrial genome sites most important for health and disease.



Keywords:  Databases; Diseases; Genetics

DOI:  https://doi.org/10.1038/d41586-024-04039-0
Heliyon. 2024 Dec 15. 10(23): e40621

Mitochondrial dysfunction of Astrocyte induces cell activation under high salt condition.

Yuemin Qiu, Gengxin Lu, Shifeng Zhang, Li Minping, Xu Xue, Wu Junyu, Zhihui Zheng, Weiwei Qi, Junjie Guo, Dongxiao Zhou, Haiwei Huang, Zhezhi Deng.

  Excess dietary sodium can accumulate in brain and adversely affect human health. We have confirmed in previous studies that high salt can induce activation of astrocyte manifested by the secretion of various inflammatory factors. In order to further explore the effect of high salt on the internal cell metabolism of astrocytes, RNA sequencing was performed on astrocytes under high salt environment, which indicated the oxidative phosphorylation and glycolysis pathways of astrocytes were downregulated. Next, we found that high salt concentrations elicited astrocyte mitochondrial morphology change, as evidenced by swelling from a short rod to a round shape through a High Intelligent and Sensitive Structured Illumination Microscope (HIS-SIM). Furthermore, we found that high salt concentrations reduced astrocyte mitochondrial oxygen consumption and membrane potential. Treatment with 18-kDa translocator protein (TSPO) ligands FGIN-1-27 improved mitochondrial networks and reversed astrocyte activation under high-salt circumstances. Our study shows that high salt can directly disrupt astrocytic mitochondrial homeostasis and function. Targeting translocator protein signaling may have therapeutic potential against high-salt neurotoxicity.

Keywords:  Astrocyte; High salt; Mitochondrial dysfunction; TSPO ligand

DOI:  https://doi.org/10.1016/j.heliyon.2024.e40621
bioRxiv. 2024 Nov 25. pii: 2024.11.22.624949. [Epub ahead of print]

Oxidative Injury to Lung Mitochondrial DNA is a Key Contributor for the Development of Chemical Lung Injury.

Shubham Dubey, Zhihong Yu, Emily Morgan Stephens, Ahmed Lazrak, Israr Ahmad, Saurabh Aggarwal, Shaida Andrabi, M Iqbal Hossain, Tamas Jilling, Solana R Fernadez, Jennifer L Bartels, Suzanne E Lapi, James Mobley, Viktor M Pastukh, Mark Gillespie, Sadis Matalon.

The mechanisms and extent to which inhalation of oxidant gases damage the mitochondrial genome contributing to the development of acute and chronic lung injury have not been investigated. C57BL/6 mice exposed to chlorine (Cl 2 ) gas and returned to room air, developed progressive loss of lung DNA glycosylase OGG1, significant oxidative injury to mtDNA, decreased intact lung mitochondrial (mt) DNA, generation of inflammatory pathway by DAMPs causing airway and alveolar injury with significant mortality. Global proteomics identified over 1400 lung proteins with alteration of key mitochondrial proteins at 24 h post Cl 2 exposure. Intranasal instillation of a recombinant protein containing mitochondrial targeted OGG1 (mitoOGG1) post exposure, decreased oxidative injury to mtDNA, lung mitochondrial proteome, severity of the acute and chronic lung injury and increased survival. These data show that injury to the mt-genome is a key contributor to the development of acute and chronic lung injury.

DOI: https://doi.org/10.1101/2024.11.22.624949
Free Radic Res. 2024 Dec 08. 1-13

Urban aerosol particulate matter promotes cellular senescence through mitochondrial ROS-mediated Akt/Nrf2 downregulation in human retinal pigment epithelial cells.

Beom Su Park, EunJin Bang, Hyun Hwangbo, Gi-Young Kim, JaeHun Cheong, Yung Hyun Choi.

  Urban aerosol particulate matter (UPM) is widespread in the environment, and its concentration continues to increase. Several recent studies have reported that UPM results in premature cellular senescence, but few studies have investigated the molecular basis of UPM-induced senescence in retinal pigment epithelial (RPE) cells. In this study, we primarily evaluated UPM-induced premature senescence and the protective function of nuclear factor erythroid 2-related factor 2 (Nrf2) in human RPE ARPE-19 cells. The findings indicated that UPM exposure substantially induced premature cellular senescence in ARPE-19 cells, as observed by increased β-galactosidase activity, expression levels of senescence-associated marker proteins, and senescence-associated phenotypes. Such UPM-induced senescence is associated with mitochondrial oxidative stress-mediated phosphatidylinositol 3'-kinase/Akt/Nrf2 downregulation. Sulforaphane-mediated Nrf2 activation Sulforaphane-mediated upregulation of phosphorylated Nrf2 suppressed the decrease in its target antioxidant gene, NAD(P)H quinone oxidoreductase 1, under UPM, which notably prevented ARPE-19 cells from UPM-induced cellular senescence. By contrast, Nrf2 knockdown exacerbated cellular senescence and promoted oxidative stress. Collectively, our results demonstrate the regulatory role of Nrf2 in UPM-induced senescence of RPE cells and suggest that Nrf2 is a potential molecular target.

Keywords:  Urban aerosol particulate matter; cellular senescence; nuclear factor erythroid-related factor 2; oxidative stress; retinal pigment epithelial cells

DOI:  https://doi.org/10.1080/10715762.2024.2438919
J Proteome Res. 2024 Dec 13.

TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach.

Meenu Maan, Neha Jaiswal, Min Liu, Harold I Saavedra, Srikumar P Chellappan, Mainak Dutta.

  Metabolic rewiring is required for cancer cells to survive in harsh microenvironments and is considered to be a hallmark of cancer. Specific metabolic adaptations are required for a tumor to become invasive and metastatic. Cell division and metabolism are inherently interconnected, and several cell cycle modulators directly regulate metabolism. Here, we report that TBK1, which is a noncanonical IKK kinase with known roles in cell cycle regulation and TLR signaling, affects cellular metabolism in cancer cells. While TBK1 is reported to be overexpressed in several cancers and its enhanced protein level correlates with poor prognosis, the underlying molecular mechanism involved in the tumor-promoting role of TBK1 is not fully understood. In this study, we show a novel role of TBK1 in regulating cancer cell metabolism using combined metabolomics, transcriptomics, and pharmacological approaches. We find that TBK1 mediates the regulation of nucleotide and energy metabolism through aldo-keto reductase B10 (AKRB10) and thymidine phosphorylase (TYMP) genes, suggesting that this TBK1-mediated metabolic rewiring contributes to its oncogenic function. In addition, we find that TBK1 inhibitors can act synergistically with AKRB10 and TYMP inhibitors to reduce cell viability. These findings raise the possibility that combining these inhibitors might be beneficial in combating cancers that show elevated levels of TBK1.

Keywords:  AKR1B10; TBK1; TYMP; cancer metabolism; drug synergy; metabolomics; omics

DOI:  https://doi.org/10.1021/acs.jproteome.4c00530
Genet Med Open. 2024 ;2 101859

Expanded-access use of elamipretide in a critically ill patient with Barth syndrome.

Amy C Goldstein, Cassandra Pantano, Mariya Redko, Laura E MacMullen, Katsuhide Maeda, Matthew J O'Connor.



Keywords:  Barth syndrome; Cardiolipin; Cardiomyopathy; Elamipretide; Mitochondria

DOI:  https://doi.org/10.1016/j.gimo.2024.101859
bioRxiv. 2024 Nov 26. pii: 2024.11.25.625228. [Epub ahead of print]

Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake.

Neeraj K Rai, Anthony M Balynas, Melissa Js MacEwen, Ashley R Bratt, Yasemin Sancak, Dipayan Chaudhuri.

Mitochondrial Ca 2+ levels are regulated to balance stimulating respiration against the harm of Ca 2+ overload. Contributing to this balance, the main channel transporting Ca 2+ into the matrix, the mitochondrial Ca 2+ uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous to the pore-forming subunit MCU, but when present in the pore-lining tetramer, inhibits Ca 2+ transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB-dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N-terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca 2+ uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca 2+ uptake, suggesting the mechanism of inhibition may involve global rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca 2+ influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca 2+ transport is consistent with MCUB retaining the highly-conserved selectivity filter DIME sequence. Finally, we apply live-cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca 2+ transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca 2+ uptake.

DOI: https://doi.org/10.1101/2024.11.25.625228
Nat Commun. 2024 Dec 13. 15(1): 10681

Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.

Xue Pan, Yun Zhao, Yucong Li, Jiajia Chen, Wenya Zhang, Ling Yang, Yuanyi Zhou Xiong, Yuqing Ying, Hao Xu, Yuhong Zhang, Chong Gao, Yuhan Sun, Nan Li, Liangyi Chen, Zhixing Chen, Kai Lei.

Tissue regeneration is a complex process involving large changes in cell proliferation, fate determination, and differentiation. Mitochondrial dynamics and metabolism play a crucial role in development and wound repair, but their function in large-scale regeneration remains poorly understood. Planarians offer an excellent model to investigate this process due to their remarkable regenerative abilities. In this study, we examine mitochondrial dynamics during planarian regeneration. We find that knockdown of the mitochondrial fusion gene, opa1, impairs both tissue regeneration and stem cell pluripotency. Interestingly, the regeneration defects caused by opa1 knockdown are rescued by simultaneous knockdown of the mitochondrial fission gene, drp1, which partially restores mitochondrial dynamics. Furthermore, we discover that Mitolow stem cells exhibit an enrichment of pluripotency due to their fate choices at earlier stages. Transcriptomic analysis reveals the delicate mitonuclear balance in metabolism and mitochondrial proteins in regeneration, controlled by mitochondrial dynamics. These findings highlight the importance of maintaining mitochondrial dynamics in large-scale tissue regeneration and suggest the potential for manipulating these dynamics to enhance stem cell functionality and regenerative processes.

DOI: https://doi.org/10.1038/s41467-024-54720-1