bims-mitmed 2025-08-24 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–08–24
twelve papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial transplants make healthy babies.
Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death.
A baby benefits from personalized gene editing in the clinic.
Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.
Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.
AMPK: Accumulating Evidence in Support of its role in Dual Regulation of Vascular Function and Metabolism During Human Pregnancy.
Cyanide overproduction impairs cellular bioenergetics in Down syndrome.
Diagnosing Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome in a Young Adult Female Patient With Seizures and Lactic Acidosis.
Unconventional myosin VI is involved in regulation of muscle energy metabolism.
Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.
Placental network differences among obstetric syndromes identified with an integrated multiomics approach.
Brain Abnormalities in Children Exposed Prenatally to the Pesticide Chlorpyrifos.

Nat Biotechnol. 2025 Aug 19.

Mitochondrial transplants make healthy babies.

Laura DeFrancesco.

DOI: https://doi.org/10.1038/s41587-025-02799-2
Dis Model Mech. 2025 Aug 01. pii: dmm052374. [Epub ahead of print]18(8):

Loss of Drosophila ribosomal protein S6 kinase II causes mitochondrial dysfunction and cell death.

Ting Deng, Lajos Kalmar, Samantha Loh, Olivier E Pardo, L Miguel Martins.

  Mitochondria are dynamic organelles that are critical for energy production in high-demand tissues, such as the brain and muscle, with fusion and fission maintaining network integrity. The dysregulation of these processes underlies pathologies, such as neurodegenerative diseases. Ribosomal S6 kinases (RSK1-4) are effectors of extracellular signal-regulated kinases (ERKs), with roles in cell survival and metabolism. Here, we show that RSKs are essential for mitochondrial health. In human cells, siRNAs targeting any RSK isoform (RSK1-4) induced mitochondrial fragmentation and reduced viability. In Drosophila melanogaster, CRISPR-mediated loss of S6kII (the sole RSK orthologue) caused mitochondrial dysfunction and tissue degeneration in high-energy-demand organs, including the indirect flight muscle and brain, accompanied by autophagic activation. Notably, we rescued these defects by expressing human RSK4, underscoring functional conservation. Our findings establish RSKs as critical regulators of mitochondrial integrity, linking ERK signalling to organelle dynamics. This work identifies RSKs as regulators of mitochondrial health in energy-demanding tissues, providing insights into the mechanisms underlying neurodegeneration and strategies to target ERK/RSK-driven mitochondrial dysfunction.

Keywords:   Drosophila ; Cell death; Kinase; Mitochondria

DOI:  https://doi.org/10.1242/dmm.052374
Nature. 2025 Aug;644(8078): 884-885

A baby benefits from personalized gene editing in the clinic.

Laura Sepp-Lorenzino.



Keywords:  Genetics; Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-025-02590-y
J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

   BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords:  Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI:  https://doi.org/10.1186/s12929-025-01153-7
iScience. 2025 Sep 19. 28(9): 113233

Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.

Tadahiro Shimazu, Ayane Kataoka, Takehiro Suzuki, Naoshi Dohmae, Yoichi Shinkai.

  Protein acetylation plays crucial roles in diverse biological functions, including mitochondrial metabolism. Although SIRT3 catalyzes the removal of acetyl groups in mitochondria, the addition of the acetyl groups is thought to be primarily controlled in an enzyme-independent manner due to the absence of potent acetyltransferases. In this study, we developed an engineered mitochondria-localized acetyltransferase, named engineered mitochondrial acetyltransferase (eMAT). eMAT localized in the mitochondrial matrix and introduced robust global protein lysine acetylation, including 413 proteins with 1,119 target lysine residues. Notably, 74% of the acetylated proteins overlapped with previously known acetylated proteins, indicating that the eMAT-mediated acetylation system is physiologically relevant. Functionally, eMAT negatively regulated mitochondrial energy metabolism, inhibited cell growth, and promoted cellular senescence, suggesting that mitochondrial hyper-acetylation drives metabolic inhibition and cellular senescence. SIRT3 counteracted eMAT-induced acetylation and metabolic inhibition, restored cell growth, and protected cells from senescence, highlighting the contribution of SIRT3 in maintaining energy metabolism and preventing cellular senescence.

Keywords:  Metabolic flux analysis; Metabolomics; Protein

DOI:  https://doi.org/10.1016/j.isci.2025.113233
Acta Physiol (Oxf). 2025 Sep;241(9): e70093

AMPK: Accumulating Evidence in Support of its role in Dual Regulation of Vascular Function and Metabolism During Human Pregnancy.

Lorna G Moore, Stephanie R Wesolowski, Ramón A Lorca, Colleen G Julian.

  Adenosine monophosphate-activated protein kinase (AMPK) serves to match perfusion with metabolism. Since pregnancy necessitates significant changes in both perfusion and metabolism for supporting fetal growth, surprising is that AMPK has received scant attention during pregnancy, perhaps due to the complexity of its actions and multiple maternal, placental, and fetal targets. Here we review human as well as experimental animal studies documenting AMPK activation's broad-ranging maternal effects. Emphasized are those affecting vascular control and blood flow to the uteroplacental circulation under conditions of chronic hypoxia. Time and dosage-dependent effects on the placenta and the fetus are also reviewed, revealing that AMPK activation affects all three-maternal, placental, and fetal-pregnancy compartments. We point to the need for an integrated study of AMPK's effects in each compartment during normal as well as fetal growth-restricted (FGR) pregnancies. Since there are currently no therapies for FGR apart from early delivery, whereas there are drugs or nutritional substances activating AMPK approved for human use, such agents may represent new treatments. However, understanding their molecular mechanisms and specific actions in pregnancy compartments is required before conducting such trials.

Keywords:  blood flow; carbohydrate metabolism; fetal growth restriction; high altitude; hypoxia; preeclampsia

DOI:  https://doi.org/10.1111/apha.70093
Neurotherapeutics. 2025 Aug 18. pii: S1878-7479(25)00197-7. [Epub ahead of print] e00719

Cyanide overproduction impairs cellular bioenergetics in Down syndrome.

Maria Petrosino, Karim Zuhra, Anna Kieronska-Rudek, Lucia Janickova, Olivier Bremer, Moustafa Khalaf, Brian A Logue, Csaba Szabo.

  Cyanide exerts its toxic effects primarily by inhibiting mitochondrial Complex IV (Cytochrome c oxidase, CCOx). Recent studies have shown that mammalian cells can endogenously produce cyanide from glycine via a lysosomal pathway. At low concentrations, cyanide may play regulatory roles, but at higher levels, it causes metabolic inhibition. Here we show that Down syndrome (DS) cells and tissues exhibit significant overproduction of cyanide, contributing to cellular metabolic suppression. DS rats show elevated blood cyanide levels, and their tissues generate more cyanide than wild-type controls-both under basal conditions and following glycine supplementation. Similarly, human DS fibroblasts produce higher levels of cyanide than healthy control cells. We attribute this increased cyanide production in DS to the marked downregulation of thiosulfate sulfurtransferase (TST, also known as rhodanese), the key enzyme responsible for cyanide detoxification. Importantly, suppression of lysosomal cyanide production in DS cells (through cyanide scavengers, lysosomal deacidification, or inhibition of serine/glycine conversion) improves cellular bioenergetics and/or enhances cell proliferation rates. Previous work has implicated excessive hydrogen sulfide (H2S) production, another endogenous gaseous signaling molecule that inhibits CCOx, in DS-associated metabolic suppression. Our current findings indicate that cyanide overproduction may also contribute to this dysfunction. Cyanide and H2S may act cooperatively on the same molecular target. These results open the possibility of developing therapeutic strategies that target cyanide or both cyanide and H2S to counteract DS-associated metabolic impairment.

Keywords:  Bioenergetics; Gasotransmitters; Mitochondria

DOI:  https://doi.org/10.1016/j.neurot.2025.e00719
Cureus. 2025 Jul;17(7): e88031

Diagnosing Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome in a Young Adult Female Patient With Seizures and Lactic Acidosis.

Ishan A Sane, Jessica R Gupte.

  The aim of this case report is to highlight the diagnostic challenges and clinical presentation of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, which is a rare, maternally inherited mitochondrial disorder. MELAS typically manifests with a constellation of neurological and systemic symptoms, including seizures, lactic acidosis, stroke-like episodes, and progressive cognitive decline. Mutations in mitochondrial DNA impair oxidative phosphorylation and result in widespread cellular dysfunction. We report the case of a 33-year-old female patient who presented with seizures, altered mental status, and focal neurological deficits. Laboratory evaluation revealed elevated serum lactate, and neuroimaging demonstrated stroke-like lesions not confined to vascular territories. A muscle biopsy showed abnormal mitochondrial accumulation, and electron microscopy detected ragged red fibers, which is confirmatory of mitochondrial cytopathy. The patient was managed symptomatically in the intensive care unit with antiepileptics, corticosteroids, and a mitochondrial cocktail comprising coenzyme Q10, L-arginine, L-carnitine, and B-complex vitamins. Plasmapheresis was also performed during initial management due to diagnostic uncertainty. The patient showed gradual clinical improvement and was discharged on supportive therapy. This case emphasizes the importance of early recognition of atypical stroke-like presentations and metabolic derangements in young patients. MELAS syndrome should be considered in the differential diagnosis of stroke mimics, especially in the absence of vascular risk factors. Timely diagnosis, supportive care, and long-term follow-up, including genetic counselling, are essential for optimizing outcomes in these patients.

Keywords:  encephalomyopathy; lactic acidosis; melas syndrome; mitochondrial disorder; red ragged fibers; stroke-like episodes

DOI:  https://doi.org/10.7759/cureus.88031
Am J Physiol Cell Physiol. 2025 Aug 18.

Unconventional myosin VI is involved in regulation of muscle energy metabolism.

Dominika Wojton, Dorota Dymkowska, Damian Matysniak, Malgorzata Topolewska, Maria Jolanta Rędowicz, Lilya Lehka.

  Mitochondria are essential for the regulation of the metabolic state of skeletal muscle, making their structure and function crucial for muscle performance. Myosin VI (MVI), an unconventional minus-end-directed motor, is expressed in skeletal muscle and myogenic cells. To explore its role in mitochondrial function and muscle metabolism, we used MVI knockout mice (Snell's waltzer, SV, MVI-KO) and their heterozygous littermates. We analyzed muscle samples from newborn (P0) and adult mice (3- and 12-months-old) and found that both MVI mRNA and protein levels were highest in newborn muscles and decreased with age. MVI expression also varied by muscle type, being highest in the slow-twitch soleus muscle (SOL) of adult mice. Loss of MVI had the most significant effects on SOL, which contains the highest number of mitochondria compared to fast-twitch muscles. MVI loss resulted in reduced respiratory capacity and ATP production in myogenic cells, indicating impaired mitochondrial function. Furthermore, MVI deficiency caused a shift from glycolytic to oxidative fiber types, especially in SOL. We also observed increased phospho-AMPK levels in MVI-KO SOL across all time points, along with downregulation of the mTOR pathway and upregulation of proteins involved in lipolysis. These findings highlight MVI as a novel regulator of metabolic processes in skeletal muscle.

Keywords:  Energy metabolism; mitochondria; myogenic cell; skeletal muscle; unconventional myosin VI

DOI:  https://doi.org/10.1152/ajpcell.00300.2025
Brain. 2025 Aug 20. pii: awaf300. [Epub ahead of print]

Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.

Camila Armirola-Ricaurte, Laura Morant, Isabelle Adant, Sherifa Ahmed Hamed, Menelaos Pipis, Stephanie Efthymiou, Silvia Amor-Barris, Derek Atkinson, Liedewei Van de Vondel, Aleksandra Tomic, Sara Seneca, Els de Vriendt, Stephan Zuchner, Bart Ghesquiere, Michael Hanna, Henry Houlden, Michael P Lunn, Mary M Reilly, Vedrana Milic Rasic, Albena Jordanova.

  Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals from three families. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18. All eight affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

Keywords:  CMT; complex IV deficiency; cytochrome c oxidase assembly factor 18

DOI:  https://doi.org/10.1093/brain/awaf300
Commun Biol. 2025 Aug 18. 8(1): 1239

Placental network differences among obstetric syndromes identified with an integrated multiomics approach.

Samantha N Piekos, Oren Barak, Andrew Baumgartner, Tianjiao Chu, W Tony Parks, Jennifer Hadlock, Leroy Hood, Nathan D Price, Yoel Sadovsky.

The placenta is essential for pregnancy, and its dysfunction can harm both mother and fetus. To better understand placental physiology and its disruption in disease, we employ a multiomics approach (transcriptomics, metabolomics, and proteomics) combined with clinical data and histopathology from 321 placentas across conditions: severe fetal growth restriction (FGR), FGR with hypertension (FGR + HDP), severe preeclampsia (PE), and spontaneous preterm delivery (PTD). Cellular deconvolution reveals FGR + HDP placentas have more extravillous trophoblasts than controls (p < 0.0001). After adjusting for fetal sex and gestational age, we build condition-specific interomics networks and detect communities (a.k.a. subnetworks). In a control community, miR-365a-3p is the most connected node, whereas in FGR + HDP placentas, it is hypoxia-induced miR-210-3p. From this community, we identify a signature containing mRNAs implicated in placental dysfunction (e.g. FLT1, FSTL3, HTRA4, LEP, and PHYHIP), which distinguishes FGR + HDP placentas from those with other conditions, illustrating the power of interomics in understanding obstetric syndromes.

DOI: https://doi.org/10.1038/s42003-025-08631-6
JAMA Neurol. 2025 Aug 18.

Brain Abnormalities in Children Exposed Prenatally to the Pesticide Chlorpyrifos.

Bradley S Peterson, Sahar Delavari, Ravi Bansal, Siddhant Sawardekar, Chaitanya Gupte, Howard Andrews, Lori A Hoepner, Wanda Garcia, Frederica Perera, Virginia Rauh.

Importance: Chlorpyrifos (CPF) is one of the most widely used insecticides throughout the world. Preclinical and clinical studies have suggested that prenatal CPF exposure is neurotoxic, but its effects on the human brain are unknown.
Objective: To identify the associations of prenatal CPF exposure with brain structure, function, and metabolism in school-aged children.
Design, Setting, and Participants: This prospective, longitudinal pregnancy cohort study was conducted from January 1998 to July 2015, with data analysis from February 2018 to November 2024 in a community in northern Manhattan and South Bronx, New York. Of 727 pregnant women of African American or Dominican descent in the original community cohort, 512 had CPF levels measured at delivery. Offspring 6 years and older were approached for magnetic resonance imaging (MRI) scanning.
Exposure: Prenatal CPF exposure.
Main Outcomes and Measures: Anatomical MRI measures of cortical thickness and local white matter volumes, diffusion tensor imaging indices of tissue microstructure, MR spectroscopy indices of neuronal density, arterial spin labeling measures of regional cerebral blood flow, and cognitive performance measures. Prespecified hypotheses before data collection included CPF-related structural abnormalities in frontotemporal cortices, basal ganglia, and white matter pathways interconnecting them, and reduced neuronal density.
Results: Participants included 270 youths (123 boys and 147 girls) aged 6.0 to 14.7 years (mean [SD] age, 10.38 [1.12] years) with self-identified Dominican or African American mothers. Progressively higher prenatal CPF exposure levels associated significantly in childhood with progressively thicker frontal, temporal, and posteroinferior cortices; reduced white matter volumes in the same regions; higher fractional anisotropy and lower diffusivity in internal capsule white matter; lower regional blood flow throughout the brain; lower indices of neuronal density in deep white matter tracts; and poorer performance on fine motor (β, -0.30; t261 = -5.0; P < .001) and motor programming (β, -0.27; t261 = -4.36; P < .001) tasks.
Conclusions and Relevance: Prenatal CPF exposure was associated with altered differentiation of neuronal tissue into cortical gray and white matter, increased myelination of the internal capsule, poorer motor performance, and profoundly impaired neuronal metabolism throughout the brain. CPF is known to increase oxidative stress and inflammation and in turn impair mitochondrial functioning, neuronal development, and maturation of the oligodendrocyte precursor cells responsible for axonal myelination. These molecular and cellular effects of CPF likely account at least in part for the observed associations of CPF with poorer long-term brain and motor outcomes.

DOI: https://doi.org/10.1001/jamaneurol.2025.2818