bims-mitdis 2025-01-12 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2025–01–12
forty-two papers selected by
Catalina Vasilescu, Helmholz Munich

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.
Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex.
Precursor occupancy controls mitochondrial import channel via proteolysis.
COA5 has an essential role in the early stage of mitochondrial complex IV assembly.
Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.
Mitochondrial diseases: from molecular mechanisms to therapeutic advances.
Triacylglycerol mobilization underpins mitochondrial stress recovery.
Mitochondria- and ER-associated actin are required for mitochondrial fusion.
Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.
Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?
Cell-Penetrating Peptide Enhances Tafazzin Gene Therapy in Mouse Model of Barth Syndrome.
Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency.
Formation of I2+III2 supercomplex rescues respiratory chain defects.
Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
GREGoR: Accelerating Genomics for Rare Diseases.
Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease.
Triheptanoin use for severe neonatal cardiomyopathy secondary to mitochondrial trifunctional protein deficiency: a first report.
Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.
The Mitochondrial Brown Adipose Tissue Maintenance Factor Nipsnap1 Interfaces Directly with the Beta-Oxidation Protein Machinery.
Tau association with synaptic mitochondria coincides with energetic dysfunction and excitatory synapse loss in the P301S tauopathy mouse model.
MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.
NAC regulates metabolism and cell fate in intestinal stem cells.
In vivo changes in zebrafish anesthetic sensitivity in response to the loss of kif5Aa are associated with the alteration of mitochondrial motility.
Site-saturation mutagenesis of 500 human protein domains.
Mitochondrial YME1L1 governs unoccupied protein translocase channels.
G6PD deficiency triggers dopamine loss and the initiation of Parkinson's disease pathogenesis.
Liberalism and mitochondrial replacement technique.
Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.
A protein interaction map of the myosin Myo2 reveals a role of Alo1 in mitochondrial inheritance in yeast.
C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN).
Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.
Coenzyme Q10 deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons.
The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.
The AI tool that can interpret any spreadsheet instantly.
We need to talk about human genome editing.
Circadian rhythms are set by epigenetic marks in neurons.
Coverage bias in small molecule machine learning.
Park7 deletion leads to sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes.
Career pathways, part 16.

medRxiv. 2024 Dec 26. pii: 2024.12.22.24319370. [Epub ahead of print]

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium

Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.
Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available. A cohort of 6,660 rare disease families were analyzed (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium as well as other rare disease cohorts.
Results: Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (one large deletion, eight reported pathogenic variants, one novel pathogenic variant). In one additional undiagnosed proband, the detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a novel de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair.
Conclusion: mtDNA variant calling from data generated by exome and genome sequencing for nuclear variant analysis resulted in a genetic diagnosis or detection of a candidate variant for 0.4% of undiagnosed families affected by a broad range of rare diseases.

DOI: https://doi.org/10.1101/2024.12.22.24319370
Genes (Basel). 2024 Nov 28. pii: 1534. [Epub ahead of print]15(12):

Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex.

Sahil Jain, Eyal Paz, Abdussalam Azem.

  The human mitochondrial proteome comprises approximately 1500 proteins, with only 13 being encoded by mitochondrial DNA. The remainder are encoded by the nuclear genome, translated by cytosolic ribosomes, and subsequently imported into and sorted within mitochondria. The process of mitochondria-destined protein import is mediated by several intricate protein complexes distributed among the four mitochondrial compartments. The focus of this mini-review is the translocase of the inner membrane 23 (TIM23) complex that assists in the import of ~60% of the mitochondrial proteome, which includes the majority of matrix proteins as well as some inner membrane and intermembrane space proteins. To date, numerous pathogenic mutations have been reported in the genes encoding various components of the TIM23 complex. These diseases exhibit mostly developmental and neurological defects at an early age. Interestingly, accumulating evidence supports the possibility that the gene for Tim50 represents a hotspot for disease-causing mutations among core TIM23 complex components, while genes for the mitochondrial Hsp70 protein (mortalin) and its J domain regulators represent hotspots for mutations affecting presequence translocase-associated motor (PAM) subunits. The potential mechanistic implications of the discovery of disease-causing mutations on the function of the TIM23 complex, in particular Tim50, are discussed.

Keywords:  TIM23 complex; Timm50; mitochondrial protein import; rare genetic disorders

DOI:  https://doi.org/10.3390/genes15121534
Nat Cell Biol. 2025 Jan 08.

Precursor occupancy controls mitochondrial import channel via proteolysis.

DOI: https://doi.org/10.1038/s41556-024-01575-9
Life Sci Alliance. 2025 Mar;pii: e202403013. [Epub ahead of print]8(3):

COA5 has an essential role in the early stage of mitochondrial complex IV assembly.

Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie S Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor.

Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.

DOI: https://doi.org/10.26508/lsa.202403013
Commun Biol. 2025 Jan 09. 8(1): 24

Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.

Julie Faitg, Tracey Davey, Ross Laws, Conor Lawless, Helen Tuppen, Eric Fitton, Doug Turnbull, Amy E Vincent.

Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do so in situ and none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in COX-positive and intermediate-fibres and that the spatial pattern is less clear in COX-deficient fibres.

DOI: https://doi.org/10.1038/s42003-024-07389-7
SLAS Discov. 2025 Jan 06. pii: S2472-5552(25)00001-2. [Epub ahead of print] 100208

Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.

Marcus Y Chin, David A Joy, Madhuja Samaddar, Anil Rana, Johann Chow, Takashi Miyamoto, Meredith Calvert.

  Mitochondria undergo dynamic morphological changes depending on cellular cues, stress, genetic factors, or disease. The structural complexity and disease-relevance of mitochondria have stimulated efforts to generate image analysis tools for describing mitochondrial morphology for therapeutic development. Using high-content analysis, we measured multiple morphological parameters and employed unbiased feature clustering to identify the most robust pair of texture metrics that described mitochondrial state. Here, we introduce a novel image analysis pipeline to enable rapid and accurate profiling of mitochondrial morphology in various cell types and pharmacological perturbations. We applied a high-content adapted implementation of our tool, MitoProfilerHC, to quantify mitochondrial morphology changes in i) a mammalian cell dose response study and ii) compartment-specific drug effects in primary neurons. Next, we expanded the usability of our pipeline by using napari, a Python-powered image analysis tool, to build an open-source version of MitoProfiler and validated its performance and applicability. In conclusion, we introduce MitoProfiler as both a high-content-based and an open-source method to accurately quantify mitochondrial morphology in cells, which we anticipate to greatly facilitate mechanistic discoveries in mitochondrial biology and disease.

Keywords:  Mitochondria; high-content imaging; high-throughput screening; image analysis; mitochondrial morphology; napari plugin; neurons; open-source

DOI:  https://doi.org/10.1016/j.slasd.2025.100208
Signal Transduct Target Ther. 2025 Jan 10. 10(1): 9

Mitochondrial diseases: from molecular mechanisms to therapeutic advances.

Haipeng Wen, Hui Deng, Bingyan Li, Junyu Chen, Junye Zhu, Xian Zhang, Shigeo Yoshida, Yedi Zhou.

Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.

DOI: https://doi.org/10.1038/s41392-024-02044-3
Nat Cell Biol. 2025 Jan 08.

Triacylglycerol mobilization underpins mitochondrial stress recovery.

Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.

Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41556-024-01586-6
Nat Commun. 2025 Jan 07. 16(1): 451

Mitochondria- and ER-associated actin are required for mitochondrial fusion.

Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.

Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.

DOI: https://doi.org/10.1038/s41467-024-55758-x
J Cell Biol. 2025 Mar 03. pii: e202404084. [Epub ahead of print]224(3):

Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.

Agustian Surya, Blythe Marie Bolton, Reed Rothe, Raquel Mejia-Trujillo, Amanda Leonita, Qiuxia Zhao, Alia Arya, Yue Liu, Rekha Rangan, Yasash Gorusu, Pamela Nguyen, Can Cenik, Elif Sarinay Cenik.

The interplay between ribosomal protein (RP) composition and mitochondrial function is essential for energy homeostasis. Balanced RP production optimizes protein synthesis while minimizing energy costs, but its impact on mitochondrial functionality remains unclear. Here, we investigated haploinsufficiency for RP genes (rps-10, rpl-5, rpl-33, and rps-23) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Significant mitochondrial morphological differences, upregulation of glutathione transferases, and SKN-1-dependent oxidative stress resistance were observed across mutants. Loss of a Datasingle rps-10 copy reduced mitochondrial activity, energy levels, and oxygen consumption, mirrored by similar reductions in mitochondrial activity and energy levels in lymphoblast cells with 50% lower RPS10 transcripts. Both systems exhibited altered translation efficiency (TE) of mitochondrial electron transport chain components, suggesting a conserved mechanism to adjust mitochondrial protein synthesis under ribosomal stress. Finally, mitochondrial membrane and cytosolic RPs showed significant RNA and TE covariation in lymphoblastoid cells, highlighting the interplay between protein synthesis machinery and mitochondrial energy production.

DOI: https://doi.org/10.1083/jcb.202404084
Biochim Biophys Acta Mol Cell Res. 2025 Jan 05. pii: S0167-4889(25)00005-9. [Epub ahead of print] 119900

A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.

Martin Hirtl, Benjamin Gottschalk, Olaf A Bachkoenig, Furkan E Oflaz, Corina Madreiter-Sokolowski, Morten Andre Høydal, Wolfgang F Graier.

  The uptake of Ca2+ by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca2+ elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca2+. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.

Keywords:  Inner mitochondrial membrane (IMM); Mitochondrial calcium uniporter (MCU); Mitochondrial calcium uptake 1 (MICU1); Stimulated-emission depletion (STED); Structured illumination microscopy (SIM)

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119900
Biochemistry. 2025 Jan 04.

Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?

Roshika Ravi, Deepsikha Routray, Radhakrishnan Mahalakshmi.

  The mitochondrial outer membrane (OMM) β-barrel proteins link the mitochondrion with the cytosol, endoplasmic reticulum, and other cellular membranes, establishing cellular homeostasis. Their active insertion and assembly in the outer mitochondrial membrane is achieved in an energy-independent yet highly effective manner by the Sorting and Assembly Machinery (SAM) of the OMM. The core SAM constituent is the 16-stranded transmembrane β-barrel Sam50. For over two decades, the primary role of Sam50 has been linked to its function as a chaperone in the OMM, wherein it assembles all β-barrels through a lateral gating and β-barrel switching mechanism. Interestingly, recent studies have demonstrated that despite its low copy number, Sam50 performs various diverse functions beyond assembling β-barrels. This includes maintaining cristae morphology, bidirectional lipid shuttling between the ER and mitochondrial inner membrane, import of select proteins, regulation of PINK1-Parkin function, and timed trigger of cell death. Given these multifaceted critical regulatory functions of SAM across all eukaryotes, we now reason that SAM merely moonlights as the hub for β-barrel biogenesis and has indeed evolved a diverse array of primary roles in maintaining mitochondrial function and cellular homeostasis.

Keywords:  MERCS; Sam50; barrel biogenesis; lipid transport; membrane protein folding; mitochondrial chaperone

DOI:  https://doi.org/10.1021/acs.biochem.4c00727
Int J Mol Sci. 2024 Dec 18. pii: 13560. [Epub ahead of print]25(24):

Cell-Penetrating Peptide Enhances Tafazzin Gene Therapy in Mouse Model of Barth Syndrome.

Rahul Raghav, Junya Awata, Gregory L Martin, Douglas Strathdee, Robert M Blanton, Michael T Chin.

  Barth Syndrome (BTHS) is an early onset, lethal X-linked disorder caused by a mutation in tafazzin (TAFAZZIN), a mitochondrial acyltransferase that remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL) and is essential for normal mitochondrial, cardiac, and skeletal muscle function. Current gene therapies in preclinical development require high levels of transduction. We tested whether TAFAZZIN gene therapy could be enhanced with the addition of a cell-penetrating peptide, penetratin (Antp). We found that TAFAZZIN-Antp was more effective than TAFAZZIN at preventing the development of pathological cardiac hypertrophy and heart failure. These findings indicate that a cell-penetrating peptide enhances gene therapy for BTHS.

Keywords:  barth syndrome; cardiolipin; cell-penetrating peptide; gene therapy; tafazzin

DOI:  https://doi.org/10.3390/ijms252413560
Biomolecules. 2024 Dec 22. pii: 1649. [Epub ahead of print]14(12):

Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.

Lydia Shen, Ulf Dettmer.

  The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson's disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease's hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy.

Keywords:  PGC-1α; PINK1/Parkin; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fragmentation; mitophagy; α-synuclein

DOI:  https://doi.org/10.3390/biom14121649
Mol Genet Metab Rep. 2025 Mar;42 101176

Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency.

María Alcázar-Fabra, Elsebet Østergaard, Daniel J M Fernández-Ayala, María Andrea Desbats, Valeria Morbidoni, Laura Tomás-Gallado, Laura García-Corzo, María Del Mar Blanquer-Roselló, Abigail K Bartlett, Ana Sánchez-Cuesta, Lucía Sena, Ana Cortés-Rodríguez, María Victoria Cascajo-Almenara, David J Pagliarini, Eva Trevisson, Sabine W Gronborg, Gloria Brea-Calvo.

   Background and aims: Primary Coenzyme Q (CoQ) deficiency caused by COQ4 defects is a clinically heterogeneous mitochondrial condition characterized by reduced levels of CoQ10 in tissues. Next-generation sequencing has lately boosted the genetic diagnosis of an increasing number of patients. Still, functional validation of new variants of uncertain significance is essential for an adequate diagnosis, proper clinical management, treatment, and genetic counseling.
Materials and methods: Both fibroblasts from a proband with COQ4 deficiency and a COQ4 knockout cell model have been characterized by a combination of biochemical and genetic analysis (HPLC lipid analysis, Oxygen consumption, minigene analysis, RNAseq, among others).
Results: Here, we report the case of a subject harboring a new variant of the COQ4 gene in compound heterozygosis, which shows severe clinical manifestations. We present the molecular characterization of this new pathogenic variant affecting the splicing of COQ4.
Conclusion: Our results highlight the importance of expanding the genetic analysis beyond the coding sequence to reduce the misdiagnosis of primary CoQ deficiency patients.

Keywords:  COQ4; Coenzyme Q10 deficiency; Hybrid minigene; Mitochondrial disorder; Spliceogenic variant; WES

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101176
Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]

Formation of I2+III2 supercomplex rescues respiratory chain defects.

Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R L Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A Stroud, James A Letts, Lena Ho.

  Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.

Keywords:  complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex

DOI:  https://doi.org/10.1016/j.cmet.2024.11.011
Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00487-X. [Epub ahead of print]37(1): 5-6

Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.

Sijie Tan, Nora Kory.

Mitochondria produce energy and building blocks essential for cell growth. How these competing processes are balanced and sustained during nutrient scarcity remains unclear. Ryu et al. uncover distinct mitochondrial subpopulations, one dedicated to ATP production and another to macromolecule synthesis, enabling cell growth and proliferation under nutrient-limiting conditions.

DOI: https://doi.org/10.1016/j.cmet.2024.12.006
ArXiv. 2024 Dec 18. pii: arXiv:2412.14338v1. [Epub ahead of print]

GREGoR: Accelerating Genomics for Rare Diseases.

Moez Dawood, Ben Heavner, Marsha M Wheeler, Rachel A Ungar, Jonathan LoTempio, Laurens Wiel, Seth Berger, Jonathan A Bernstein, Jessica X Chong, Emmanuèle C Délot, Evan E Eichler, Richard A Gibbs, James R Lupski, Ali Shojaie, Michael E Talkowski, Alex H Wagner, Chia-Lin Wei, Christopher Wellington, Matthew T Wheeler, GREGoR Partner Members, Claudia M B Carvalho, Casey A Gifford, Susanne May, Danny E Miller, Heidi L Rehm, Fritz J Sedlazeck, Eric Vilain, Anne O'Donnell-Luria, Jennifer E Posey, Lisa H Chadwick, Michael J Bamshad, Stephen B Montgomery, Genomics Research To Elucidate The Genetics Of Rare Diseases, Consortium.

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize, and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://gregorconsortium.org/data). The majority of these families have undergone prior clinical genetic testing but remained unsolved, with most being exome-negative. Here, we describe the collaborative research framework, datasets, and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.
Curr Alzheimer Res. 2025 Jan 08.

Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease.

Alina Chaplygina, Daria Zhdanova.

  Mitochondrial form and function are intricately linked through dynamic processes of fusion and fission, and disruptions in these processes are key drivers of neurodegenerative diseases, like Alzheimer's. The inability of mitochondria to transition between their dynamic forms is a critical factor in the development of pathological states. In this paper, we focus on the importance of different types of mitochondrial phenotypes in nervous tissue, discussing how mitochondria in Alzheimer's disease are "stuck" in certain patterns and how this pattern maintains itself. Understanding the specific roles and transitions between mitochondrial forms, including tiny, networked, and hyperfused, is crucial in developing new therapies aimed at restoring mitochondrial homeostasis. By targeting these dynamics, we may be able to intervene early in the disease process, offering novel avenues for preventing or treating neurodegeneration.

Keywords:  Alzheimer's disease.; Mitochondria; fission; fusion; mitochondrial phenotypes; mitophagy

DOI:  https://doi.org/10.2174/0115672050366194250107050650
Cardiol Young. 2025 Jan 09. 1-3

Triheptanoin use for severe neonatal cardiomyopathy secondary to mitochondrial trifunctional protein deficiency: a first report.

John-Anthony Coppola, Megan Boothe, Anna McGuinness, Yuen Lo Yau, Haley Blanchette, Michael A Brock, Mark S Bleiweis, Jeffrey P Jacobs, Giles J Peek, Dipankar Gupta.

  Mitochondrial trifunctional protein deficiency is a long-chain fatty acid disorder that may include manifestations of severe cardiomyopathy and arrhythmias. The pathophysiology for the severe presentation is unclear but is an indicator for worse outcomes. Triheptanoin, a synthetic medium chain triglyceride, has been reported to reverse cardiomyopathy in some individuals, but there is limited literature in severe cases. We describe a neonatal onset of severe disease whose clinical course was not improved despite mechanical support and triheptanoin.

Keywords:  Cardiomyopathy; ECMO; long-chain fatty acid oxidation disorder; newborn screen; trifunctional protein deficiency; triheptanoin

DOI:  https://doi.org/10.1017/S1047951124026386
Mol Genet Metab. 2024 Dec 30. pii: S1096-7192(24)00893-X. [Epub ahead of print]144(3): 109009

Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.

Charles R DiFalco, Charul Gijavanekar, Yue Wang, Alexandra N Grace, Keren Machol, Lisa Emrick, Ning Liu, Elizabeth Mizerik, Laura Mackay, Hongzheng Dai, Liesbeth Vossaert, Fan Xia, Sarah H Elsea, Fernando Scaglia.

  The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA. It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA. In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method. Here, we retrospectively evaluated a cohort of nine patients with confirmed 3-MGA-uria syndromes. It was observed that UOA analysis obtained from three separate patients did not identify detectable 3-MGA levels. This inherent limitation highlights the need for a more sensitive clinical modality. Untargeted metabolomics profiling is a rapidly emerging technology that is being used to detect and characterize biochemical abnormalities in many inborn errors of metabolism. Untargeted metabolomics profiling performed on plasma samples in this cohort identified significant elevations of 3-MGA in all nine individuals. This high degree of clinical sensitivity demonstrates the promising potential for untargeted metabolomics analysis as both an effective biochemical screening tool for 3-MGA-uria syndromes and a functional method to assist with validation of genomic variants of uncertain significance in these disorders.

Keywords:  3-methylglutaconic aciduria; Mitochondrial disorders; Untargeted metabolomics

DOI:  https://doi.org/10.1016/j.ymgme.2024.109009
bioRxiv. 2024 Dec 29. pii: 2024.12.29.630678. [Epub ahead of print]

The Mitochondrial Brown Adipose Tissue Maintenance Factor Nipsnap1 Interfaces Directly with the Beta-Oxidation Protein Machinery.

Pei-Yin Tsai, Yue Qu, Claire Walter, Yang Liu, Chloe Cheng, Joeva J Barrow.

Background: The activation of brown adipose tissue (BAT) is associated with improved metabolic health in humans. We previously identified the mitochondrial protein 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) as a novel regulatory factor that integrates with lipid metabolism and is critical to sustain the long-term activation of BAT, but the precise mechanism and function of Nipsnap1 is unknown.
Objectives: Define how the regulatory factor Nipsnap1 integrates with lipid metabolism.
Methods: We generated adeno-associated viral (AAV) constructs that overexpress Nipsnap1 in the thermogenic fat of mice. We then measured both whole-body and cellular mitochondrial metabolism and mapped the first Nipsnap1 interacting protein-protein network.
Results: Herein, we show that adipose-specific overexpression of Nipsnap1 in mice increases energy expenditure through the utilization of lipids as an energy substrate. The increase in energy expenditure results in reduced weight gain. Additionally, we show that Nipsnap1 overexpression in primary adipocytes increases lipid beta-oxidation. Moreover, we mapped the first protein- protein network of Nipsnap1 in brown adipocytes and show that Nipsnap1 interacts with proteins that regulate both peroxisomal and mitochondrial fatty acid beta-oxidation.
Conclusion: This study elucidates a mechanistic function of Nipsnap1 in thermogenic fat where Nipsnap1 facilitates a functional connection between peroxisomal and mitochondrial beta-oxidation pathways. By enhancing lipid utilization as energy substrates, Nipsnap1 plays a pivotal role in sustaining thermogenic fat activation to increase energy expenditure. These findings underscore the potential of Nipsnap1 as a therapeutic target for metabolic health.

DOI: https://doi.org/10.1101/2024.12.29.630678
Neurobiol Aging. 2024 Dec 20. pii: S0197-4580(24)00220-3. [Epub ahead of print]147 163-175

Tau association with synaptic mitochondria coincides with energetic dysfunction and excitatory synapse loss in the P301S tauopathy mouse model.

L Daniel Estrella, Andrew J Trease, Lexi Sheldon, Nashanthea J Roland, Howard S Fox, Kelly L Stauch.

  Neurodegenerative Tauopathies are a part of several neurological disorders and aging-related diseases including, but not limited to, Alzheimer's Disease, Frontotemporal Dementia with Parkinsonism, and Chronic Traumatic Encephalopathy. The major hallmarks present in these conditions include Tau pathology (composed of hyperphosphorylated Tau tangles) and synaptic loss. in vivo studies linking Tau pathology and mitochondrial alterations at the synapse, an avenue that could lead to synaptic loss, remain predominantly scarce. For this reason, using 3-month-old wild-type and human mutant Tau P301S transgenic mice, we investigated the association of Tau with mitochondria, synaptosome bioenergetics, and characterized excitatory synaptic loss across hippocampal regions (Dentate Gyrus, perisomatic CA3, and perisomatic CA1) and in the parietal cortex. We found a significant loss of excitatory synapses in the parietal cortex and hippocampal Dentate Gyrus (DG) of Tau P301S mice. Furthermore, we found that Tau (total and disease-relevant phosphorylated Tau) associates with both the non-synaptic and synaptic mitochondria of Tau P301S mice and this coincided with synaptic mitochondrial dysfunction. The findings presented here suggest that Tau associates with mitochondria at the synapse, leading to synaptic mitochondrial dysfunction, and likely contributing to synaptic loss.

Keywords:  Alzheimer’s disease; FTDP-17; Mitochondrial DNA; P301S mice; PS19 mice; Synapse loss; Synaptic mitochondria; Synaptic mitochondrial dysfunction; Tau pathology

DOI:  https://doi.org/10.1016/j.neurobiolaging.2024.12.006
Bioinform Adv. 2025 ;5(1): vbae172

MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.

Stephen Chapman, Theo Brunet, Arnaud Mourier, Bianca H Habermann.

Motivation: Mitochondria are essential for cellular metabolism and are inherently flexible to allow correct function in a wide range of tissues. Consequently, dysregulated mitochondrial metabolism affects different tissues in different ways leading to challenges in understanding the pathology of mitochondrial diseases. System-level metabolic modelling is useful in studying tissue-specific mitochondrial metabolism, yet despite the mouse being a common model organism in research, no mouse specific mitochondrial metabolic model is currently available.
Results: Building upon the similarity between human and mouse mitochondrial metabolism, we present mitoMammal, a genome-scale metabolic model that contains human and mouse specific gene-product reaction rules. MitoMammal is able to model mouse and human mitochondrial metabolism. To demonstrate this, using an adapted E-Flux algorithm, we integrated proteomic data from mitochondria of isolated mouse cardiomyocytes and mouse brown adipocyte tissue, as well as transcriptomic data from in vitro differentiated human brown adipocytes and modelled the context specific metabolism using flux balance analysis. In all three simulations, mitoMammal made mostly accurate, and some novel predictions relating to energy metabolism in the context of cardiomyocytes and brown adipocytes. This demonstrates its usefulness in research in cardiac disease and diabetes in both mouse and human contexts.
Availability and implementation: The MitoMammal Jupyter Notebook is available at: https://gitlab.com/habermann_lab/mitomammal.

DOI: https://doi.org/10.1093/bioadv/vbae172
Sci Adv. 2025 Jan 10. 11(2): eadn9750

NAC regulates metabolism and cell fate in intestinal stem cells.

Sofia Ramalho, Ferhat Alkan, Stefan Prekovic, Katarzyna Jastrzebski, Eric Pintó Barberà, Liesbeth Hoekman, Maarten Altelaar, Cecilia de Heus, Nalan Liv, Maria J Rodríguez-Colman, Mehmet Yilmaz, Rob van der Kammen, Juliette Fedry, Mark C de Gooijer, Saskia Jacoba Elisabeth Suijkerbuijk, William J Faller, Joana Silva.

Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.

DOI: https://doi.org/10.1126/sciadv.adn9750
bioRxiv. 2024 Dec 21. pii: 2024.12.20.629838. [Epub ahead of print]

In vivo changes in zebrafish anesthetic sensitivity in response to the loss of kif5Aa are associated with the alteration of mitochondrial motility.

Priya Dubey, Roshni Datta, Roderic G Eckenhoff, Victoria M Bedell.

  Anesthetic and sedative drugs are small compounds known to bind to hundreds of proteins. One intriguing binding partner of propofol is the kinesin motor domain, kif5A, a neuronal mitochondrial transport protein. Here, we used zebrafish WT and kif5Aa KO larval behavioral assays to assess anesthetic sensitivity and combined that with zebrafish primary neuronal cell culture to probe for alteration in mitochondrial motility. We found that the loss of kif5Aa increases behavioral sensitivity to propofol and etomidate, with etomidate hypersensitivity greater than propofol. In contrast, kif5Aa KO animals were resistant to the behavioral effects of dexmedetomidine. Finally, WT and kif5Aa KO larvae responded similarly to the behavioral effects of ketamine. Propofol inhibited the anterograde motility of mitochondria in WT zebrafish neurons, while etomidate inhibited mitochondrial motility in both anterograde and retrograde directions; neither drug altered mitochondrial motility in the kif5Aa knockout (KO) neurons. In contrast, dexmedetomidine enhanced retrograde mitochondrial motility in both WT and kif5Aa KO animals. Finally, ketamine had little significant effect on mitochondrial motility in either mutant or WT animals. These data demonstrate that each anesthetic/sedative drug affects the motor protein machinery uniquely and is associated with unique changes in behavior. Understanding how different anesthetic compounds alter neuron motor proteins will be important in defining how anesthetics alter neuronal signaling and energetic dynamics.

Keywords:  change in anesthetic sensitivity; kinesin; motility; motor protein; zebrafish behavior

DOI:  https://doi.org/10.1101/2024.12.20.629838
Nature. 2025 Jan 08.

Site-saturation mutagenesis of 500 human protein domains.

Antoni Beltran, Xiang'er Jiang, Yue Shen, Ben Lehner.

Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases1. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the effect of more than 500,000 variants on the abundance of more than 500 human protein domains. This dataset reveals that 60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases and is particularly important in recessive disorders. We combine stability measurements with protein language models to annotate functional sites across proteins. Mutational effects on stability are largely conserved in homologous domains, enabling accurate stability prediction across entire protein families using energy models. Our data demonstrate the feasibility of assaying human protein variants at scale and provides a large consistent reference dataset for clinical variant interpretation and training and benchmarking of computational methods.

DOI: https://doi.org/10.1038/s41586-024-08370-4
Nat Cell Biol. 2025 Jan 07.

Mitochondrial YME1L1 governs unoccupied protein translocase channels.

Meng-Chieh Hsu, Hiroki Kinefuchi, Linlin Lei, Reika Kikuchi, Koji Yamano, Richard J Youle.

Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase fused to the N terminus of the inner membrane protein MIC60. While stabilization of the dihydrofolate reductase domain by methotrexate inhibited endogenous mitochondrial protein import, it neither activated the transcription factor ATF4, nor was affected by ATAD1 expression or by VCP/p97 inhibition. On the other hand, notably, plugging the channel of translocase of the outer membrane) induced YME1L1, an ATP-dependent protease, to eliminate translocase of the inner membrane (TIM23) channel components TIMM17A and TIMM23. The data suggest that unoccupied TIM23 complexes expose a C-terminal degron on TIMM17A to YME1L1 for degradation. Import plugging caused a cell growth defect and loss of YME1L1 exacerbated the growth inhibition, showing the protective effect of YME1L1 activity. YME1L1 seems to play a crucial role in mitochondrial quality control to counteract precursor stalling in the translocase of the outer membrane complex and unoccupied TIM23 channels.

DOI: https://doi.org/10.1038/s41556-024-01571-z
Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01529-8. [Epub ahead of print]44(1): 115178

G6PD deficiency triggers dopamine loss and the initiation of Parkinson's disease pathogenesis.

Morgan G Stykel, Shehani V Siripala, Eric Soubeyrand, Carla L Coackley, Ping Lu, Suelen Camargo, Sharanya Thevasenan, Gerardo Balderas Figueroa, Raphaella W L So, Erica Stuart, Rachi Panchal, Elissavet-Kalliopi Akrioti, Jeffery T Joseph, Omid Haji-Ghassemi, Era Taoufik, Tariq A Akhtar, Joel C Watts, Scott D Ryan.

  Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.

Keywords:  CP: Neuroscience; G6PD; Parkinson's disease; alpha-synuclein; dopamine; hiPSC; oxidative stress

DOI:  https://doi.org/10.1016/j.celrep.2024.115178
J Med Ethics. 2025 Jan 09. pii: jme-2024-110373. [Epub ahead of print]

Liberalism and mitochondrial replacement technique.

Marco Tang.

  How should defenders of liberalism think about access to reproductive technologies? Mitochondrial replacement technique (MRT) enables women with pathogenic variations of mitochondrial disease to have children without the fear of transmission. This technology can also allow lesbians, or partners with female-assigned physiology (PFP), to have genetically related offspring. Cavaliere and Palacios-Gonzalez argue that lesbians should be able to access MRT on autonomy grounds. They argue MRT should not be restricted to those with mitochondrial disease because it is non-therapeutic and invokes the Millian harm principle. Yet, Baylis argues that a desire for genetically related offspring is not sufficient to access MRT because it contributes to harmful social narratives about adopted families. I strengthen Cavaliere and Palacios-Gonzalez's liberal defence by bringing another liberal commitment-equality. Ultimately, I argue that the liberal state must allow PFPs to use MRT. I first show that the use of MRT by PFPs is permissible even if MRT is therapeutic by comparing MRT with cosmetic surgery-that is, social uses of therapeutic interventions are permitted if we are interested in doing so. Borrowing from Dillard, a possible interest is self-replication. Next, I outline and respond to a possible criticism by Baylis-MRT is necessary but not sufficient for self-replication. Ultimately, I show that the liberal state must permit MRT because (a) it provides PFPs with an equal opportunity to experience having genetically related offspring with their partner and (b) contributing to harmful social narratives is insufficient for limiting autonomy.

Keywords:  Ethics- Medical; Gene Transfer Techniques; Paternalism; Personal Autonomy; Reproductive Medicine

DOI:  https://doi.org/10.1136/jme-2024-110373
J Clin Invest. 2025 Jan 09. pii: e184069. [Epub ahead of print]

Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.

Jue Li, Jie Bai, Vincent T Pham, Michihiro Hashimoto, Maiko Sezaki, Qili Shi, Qiushi Jin, Chenhui He, Amy Armstrong, Tian Li, Mingzhe Pan, Shujun Liu, Yu Luan, Hui Zeng, Paul R Andreassen, Gang Huang.

  Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of Carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoietic specific conditional knock-out (Cpt1aΔ/Δ) mouse model, we found that loss of Cpt1a leads to HSC defects, including loss of HSC quiescence and self-renewal, and increased differentiation. Mechanistically, we find that loss of Cpt1a results in elevated levels of mitochondrial respiratory chain complex components and their activities, as well as increased ATP production, and accumulation of mitochondrial reactive oxygen species (mitoROS) in HSCs. Taken together, this suggests hyperactivation of mitochondria and metabolic rewiring via upregulated glucose-fueled oxidative phosphorylation (OXPHOS). In summary, our findings demonstrate a novel role for Cpt1a in HSC maintenance and provide insight into the regulation of mitochondrial metabolism via control of the balance between FAO and glucose-fueled OXPHOS.

Keywords:  Hematology; Hematopoietic stem cells; Metabolism

DOI:  https://doi.org/10.1172/JCI184069
J Cell Sci. 2025 Jan 08. pii: jcs.263678. [Epub ahead of print]

A protein interaction map of the myosin Myo2 reveals a role of Alo1 in mitochondrial inheritance in yeast.

Xenia Chelius, Nathalie Rausch, Veronika Bartosch, Maria Klecker, Till Klecker, Benedikt Westermann.

  Budding yeast cells multiply by asymmetric cell division. During this process, the cell organelles are transported by myosin motors along the actin cytoskeleton into the growing bud, while at the same time some organelles must be retained in the mother cell. The ordered partitioning of organelles depends on highly regulated binding of motor proteins to cargo membranes. To search for novel components involved in this process, we performed a protein fragment complementation screen using the cargo binding domain of Myo2, the major organelle transporter in yeast, as a bait and a genome-wide strain collection expressing yeast proteins as prey. One robust hit was Alo1, a poorly characterized D-arabinono-1,4-lactone oxidase located in the mitochondrial outer membrane. We found that mutants lacking Alo1 exhibit defects in mitochondrial morphology and inheritance. During oxidative stress dysfunctional mitochondria are immobilized in the mother in wild type cells. Intriguingly, overexpression of ALO1 restores bud-directed transport of mitochondria under these conditions. We propose that Alo1 supports the recruitment of Myo2 to mitochondria and its activity is particularly important under oxidative stress.

Keywords:  Mitochondria; Myo2 cargo binding domain; Myosin motor; Organelle inheritance; Oxidative stress; Saccharomyces cerevisiae

DOI:  https://doi.org/10.1242/jcs.263678
Eur J Hum Genet. 2025 Jan 04.

C19orf12 gene variants causing mitochondrial membrane protein-associated neurodegeneration (MPAN).

Riyanka Kumari, Vikram V Holla, Neeharika Sriram, Nitish Kamble, Ajay Asranna, Jitender Saini, Gautham Arunachal, Ravi Yadav, Akhilesh Pandey, Pramod Kumar Pal, Babylakshmi Muthusamy.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurodegenerative disorder characterized by spastic paraplegia, parkinsonism and psychiatric and/or behavioral symptoms caused by variants in gene encoding chromosome-19 open reading frame-12 (C19orf12). We present here seven patients from six unrelated families with detailed clinical, radiological, and genetic investigations. Childhood-onset patients predominantly had a spastic ataxic phenotype with optic atrophy, while adult-onset patients were presented with cognitive, behavioral, and parkinsonian symptoms. Levodopa induced choreiform dyskinesia was observed in one patient who showed a response to levodopa. Brain magnetic resonance imaging showed mineralization in all patients and cerebellar atrophy in one patient. The "pallidal splitting sign" was found in two patients and additional caudate and putamen mineralization was noted in two patients. Exome sequencing identified six variants in the C19orf12 gene, including two novel splice-site variants, four previously reported missense variants. Transcript analysis using RT-PCR followed by Sanger sequencing was performed on a splice site variant (c.194-2delA) to understand the splice defect and its consequences. This analysis confirmed the splice defect and use of an alternate cryptic splice site in the downstream exonic region. The variants identified in this study expand the spectrum of clinical and genetic knowledge on MPAN patients, highlighting the importance of genetic testing in the diagnosis and management of this disorder.

DOI: https://doi.org/10.1038/s41431-024-01778-6
bioRxiv. 2024 Dec 27. pii: 2024.12.27.630525. [Epub ahead of print]

Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.

Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner.

Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of de novo lipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and drug candidates for both lean MASLD and support of urea cycle function in CD.

DOI: https://doi.org/10.1101/2024.12.27.630525
Free Radic Biol Med. 2025 Jan 07. pii: S0891-5849(25)00009-7. [Epub ahead of print]

Coenzyme Q10 deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons.

Alba Pesini, Eliana Barriocanal-Casado, Giacomo Monzio Compagnoni, Agustin Hidalgo-Gutierrez, Giussepe Yanez, Mohammed Bakkali, Yashpal S Chhonker, Giulio Kleiner, Delfina Larrea, Saba Tadesse, Luis Carlos Lopez, Daryl J Murry, Alessio Di Fonzo, Estela Area-Gomez, Catarina M Quinzii.

  Coenzyme Q10 (CoQ10) is a critical component of the mitochondrial respiratory chain. CoQ10 deficiencies often cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ10 involvement in several biological processes. One such process is cholesterol homeostasis, since CoQ10 is synthesized through the mevalonate pathway, which also produces cholesterol. To elucidate the role of lipid dysfunction in the pathogenesis of CoQ10 deficiency, we investigated lipid metabolism in human CoQ10 deficient iPSCs-derived neurons, and in SH-SY5Y neurons after pharmacological manipulation of the mevalonate pathway. We show that CoQ10 deficiency causes alterations in cholesterol homeostasis, fatty acids oxidation, phospholipids and sphingolipids synthesis in neurons. These alterations depend on the molecular defect, and on the residual CoQ10 levels. Our results imply that CoQ10 deficiencies can induce pathology by altering lipid homeostasis and the composition of cellular membranes. These findings provide further understanding of the mechanisms underlying CoQ10 deficiency and point to potential novel therapeutic targets.

Keywords:  COQ2; Cholesterol; Coenzyme Q(10); PDSS2; lipids

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.009
Cell Rep. 2025 Jan 09. pii: S2211-1247(24)01505-5. [Epub ahead of print]44(1): 115154

The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.

Jaromir Novak, Zuzana Nahacka, Gabriela L Oliveira, Petra Brisudova, Maria Dubisova, Sarka Dvorakova, Sona Miklovicova, Marketa Dalecka, Verena Puttrich, Lenka Grycova, Silvia Magalhaes-Novais, Catarina Mendes Correia, Jennifer Levoux, Ludek Stepanek, Jan Prochazka, David Svec, David Pajuelo Reguera, Guillermo Lopez-Domenech, Renata Zobalova, Radek Sedlacek, Mikkel G Terp, Payam A Gammage, Zdenek Lansky, Josef Kittler, Paulo J Oliveira, Henrik J Ditzel, Michael V Berridge, Anne-Marie Rodriguez, Stepana Boukalova, Jakub Rohlena, Jiri Neuzil.

  Recent research has shown that mtDNA-deficient cancer cells (ρ0 cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1KO) mice markedly delayed tumor formation after grafting ρ0 cancer cells. Miro1KO mice with fluorescently labeled mitochondria revealed that this delay was due to hindered mitochondrial transfer from the tumor stromal cells to grafted B16 ρ0 cells, which impeded recovery of mitochondrial respiration and tumor growth. Miro1KO led to the perinuclear accumulation of mitochondria and impaired mobility of the mitochondrial network. In vitro experiments revealed decreased association of mitochondria with microtubules, compromising mitochondrial transfer via tunneling nanotubes (TNTs) in mesenchymal stromal cells. Here we show the role of Miro1 in horizontal mitochondrial transfer in mouse melanoma models in vivo and its involvement with TNTs.

Keywords:  CP: Cancer; CP: Cell biology; Miro1; RHOT1; cancer; horizontal transfer of mitochondria; melanoma; mitochondria; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.celrep.2024.115154
Nature. 2025 Jan;637(8045): 274-275

The AI tool that can interpret any spreadsheet instantly.

Duncan C McElfresh.



Keywords:  Machine learning

DOI:  https://doi.org/10.1038/d41586-024-03852-x
Nature. 2025 Jan;637(8045): 252

We need to talk about human genome editing.



Keywords:  Ethics; Genomics; Health care; Society

DOI:  https://doi.org/10.1038/d41586-025-00015-4
Nature. 2025 Jan 08.

Circadian rhythms are set by epigenetic marks in neurons.

Debosmita Sardar, Tatiana G Kutateladze.



Keywords:  Animal behaviour; Brain; Epigenetics; Molecular biology

DOI:  https://doi.org/10.1038/d41586-024-04080-z
Nat Commun. 2025 Jan 09. 16(1): 554

Coverage bias in small molecule machine learning.

Fleming Kretschmer, Jan Seipp, Marcus Ludwig, Gunnar W Klau, Sebastian Böcker.

Small molecule machine learning aims to predict chemical, biochemical, or biological properties from molecular structures, with applications such as toxicity prediction, ligand binding, and pharmacokinetics. A recent trend is developing end-to-end models that avoid explicit domain knowledge. These models assume no coverage bias in training and evaluation data, meaning the data are representative of the true distribution. However, the domain of applicability is rarely considered in such models. Here, we investigate how well large-scale datasets cover the space of known biomolecular structures. For doing so, we propose a distance measure based on solving the Maximum Common Edge Subgraph (MCES) problem, which aligns well with chemical similarity. Although this method is computationally hard, we introduce an efficient approach combining Integer Linear Programming and heuristic bounds. Our findings reveal that many widely-used datasets lack uniform coverage of biomolecular structures, limiting the predictive power of models trained on them. We propose two additional methods to assess whether training datasets diverge from known molecular distributions, potentially guiding future dataset creation to improve model performance.

DOI: https://doi.org/10.1038/s41467-024-55462-w
NPJ Parkinsons Dis. 2025 Jan 04. 11(1): 8

Park7 deletion leads to sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes.

Sergio Helgueta, Tony Heurtaux, Alessia Sciortino, Yujuan Gui, Jochen Ohnmacht, Pauline Mencke, Ibrahim Boussaad, Rashi Halder, Pierre Garcia, Rejko Krüger, Michel Mittelbronn, Manuel Buttini, Thomas Sauter, Lasse Sinkkonen.

Loss-of-function mutations in PARK7, encoding for DJ-1, can lead to early onset Parkinson's disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. While at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed in 8 month-old males. The affected genes are involved in processes like focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of NRF2. Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male primary astrocytes recapitulated many of the in vivo changes, including downregulation of CYP1B1, an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes through astrocytic alterations in the NRF2-CYP1B1 axis, suggesting higher sensitivity of males to loss of DJ-1.

DOI: https://doi.org/10.1038/s41531-024-00851-7
Nat Metab. 2025 Jan 07.

Career pathways, part 16.

Cholsoon Jang, Min-Dian Li.

DOI: https://doi.org/10.1038/s42255-024-01192-8