bims-mitmed 2026-01-04 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–01–04
eleven papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.
SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging.
Mitochondrial tRNA-Derived Diseases.
When Mitochondria Falter, the Barrier Fails: Mechanisms of Inner Blood-Retinal Barrier (iBRB) Injury and Opportunities for Mitochondria-Targeted Repair.
Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
Mitochondrial quality control mechanisms as molecular targets for impaired lung development: from fetuses to neonates.
Disturbances in Mitochondrial Network, Biogenesis, and Mitochondria-Mediated Inflammatory Responses in Selected Brain Structures of Rats Exposed to Lead (Pb) During Prenatal and Neonatal Development.
Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.
Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts.
Fractal analysis of brain shape formation predicts age and genetic similarity in human newborns.
PGC-1α: key regulator of mitochondrial biogenesis and cellular differentiation in metabolic and regenerative tissues.

iScience. 2025 Dec 19. 28(12): 114204

Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.

Jong Shin, Khaled Tighanimine, Yann Cormerais, Dean M Rosenthal, Pratima Niroula, Samuel C Lapp, Krystle C Kalafut, Madi Y Cisse, Sandra Schrötter, Brendan D Manning.

  The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a sensor of growth signals that control cell growth, has been studied mainly in proliferating cells. Primary cilia are sensory organelles present on most quiescent cells and are essential for receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences primary cilia growth. Here, we show that mTORC1 promotes cilia elongation without affecting ciliogenesis by suppressing autophagy. Inhibiting mTORC1 through pharmacological, nutritional, or genetic interventions shortened primary cilia, whereas activation of the pathway elongated them. Furthermore, pharmacological or genetic inhibition of autophagy-a key downstream process blocked by mTORC1-elongated primary cilia and rendered them resistant to mTORC1 inhibition. These mTORC1-mediated effects extend to mouse neurons ex vivo and in vivo. Thus, the mTORC1-mediated regulation of autophagy controls primary cilia length and may contribute to diseases in which ciliary function is altered, referred to as ciliopathies.

Keywords:  Cell biology; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2025.114204
Genes (Basel). 2025 Dec 15. pii: 1497. [Epub ahead of print]16(12):

SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging.

Kate Šešelja, Ena Šimunić, Sandra Sobočanec, Iva I Podgorski, Marija Pinterić, Marijana Popović Hadžija, Tihomir Balog, Robert Belužić.

  Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This review synthesizes evidence showing how SIRT3 loss in select "driver tissues"-notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary-initiates systemic aging through the release of cytokines, oxidized metabolites, and extracellular vesicles. We discuss molecular routes and mediators of senescence propagation, including the senescence-associated secretory phenotype (SASP), mitochondrial-derived vesicles, and circulating mitochondrial DNA, as well as sex-specific modulation of SIRT3 by hormonal and intrinsic factors. By integrating multi-tissue and sex-dependent data, we outline a framework in which SIRT3 activity defines the mitochondrial threshold separating local adaptation from systemic aging spread. Targeting SIRT3 and its NAD+-dependent network may offer a unified strategy to restore mitochondrial quality, dampen chronic inflammation, and therefore recalibrate the aging dynamics of an organism.

Keywords:  NAD+ metabolism; SIRT3; aging drivers; extracellular vesicles; inflammaging; mitochondrial acetylation; senescence; sex differences; systemic aging

DOI:  https://doi.org/10.3390/genes16121497
Int J Mol Sci. 2025 Dec 13. pii: 12023. [Epub ahead of print]26(24):

Mitochondrial tRNA-Derived Diseases.

Antonia Petropoulou, Nikolaos Kypraios, Dimitra Rizopoulou, Adamantia Kouvela, Alexandros Maniatis, Katerina Anastasopoulou, Alexandra Anastogianni, Theodoros Korfiatis, Katerina Grafanaki, Vassiliki Stamatopoulou, Constantinos Stathopoulos.

  Mitochondrial tRNA genes are critical hotspots for pathogenic mutations and several mitochondrial diseases. They account for approximately 70-75% of disease-causing mtDNA variants despite comprising only 5-10% of the mitochondrial genome. These mutations interfere with mitochondrial translation and affect oxidative phosphorylation, resulting in remarkably heterogeneous multisystem disorders. Under this light, we systematically reviewed PubMed, Scopus, and MITOMAP databases through October 2025, indexing all clinically relevant pathogenic mt-tRNA mutations classified by affected organ systems and underlying molecular mechanisms. Approximately 500 distinct pathogenic variants were identified across all 22 mt-tRNA genes. Beyond typical syndromes like MELAS, MERRF, Leigh syndrome, and Kearns-Sayre syndrome that are linked to mt-tRNA mutations, they increasingly implicate cardiovascular diseases (cardiomyopathy, hypertension), neuromuscular disorders (myopathies, encephalopathies), sensory impairment (hearing loss, optic neuropathy), metabolic dysfunction (diabetes, polycystic ovary syndrome), renal disease, neuropsychiatric conditions, and cancer. Beyond sequence mutations, defects in post-transcriptional modification systems emerge as critical disease mechanisms affecting mt-tRNA function and stability. The mutations on tRNA genes described herein represent potential targets for emerging genome editing therapies, although several translational challenges remain. However, targeted correction of pathogenic mt-tRNA mutations holds transformative potential for precision intervention on mitochondrial diseases.

Keywords:  human diseases; mitochondrial tRNA; mt-tRNA modifications; mtDNA mutations

DOI:  https://doi.org/10.3390/ijms262412023
Int J Mol Sci. 2025 Dec 12. pii: 11984. [Epub ahead of print]26(24):

When Mitochondria Falter, the Barrier Fails: Mechanisms of Inner Blood-Retinal Barrier (iBRB) Injury and Opportunities for Mitochondria-Targeted Repair.

Ziyi Chen, Qianzi Jin, Jiajun Li, Keran Li.

  As the central hub of retinal metabolism, mitochondria are vital for sustaining the integrity of the inner blood-retinal barrier (iBRB), which is fundamental to retinal homeostasis. Mitochondrial dysfunction accelerates severe iBRB disruption, a process which is increasingly implicated in a cascade of mitochondrial pathologies including mitochondrial DNA destabilization, oxidative stress, calcium homeostasis disruption, mitochondrial autophagy deficiency, and dysregulated dynamic regulation. This review establishes the iBRB as a crossroads for metabolic, redox, and inflammatory signaling. By analyzing evidence from diabetic retinopathy and retinal vein occlusion models, we clarify how mitochondrial decline translates local energy deficiency into chronic barrier dysfunction. We posit that restoring mitochondrial function is indispensable for vascular resilience and regeneration, a conclusion drawn from integrating molecular, cellular, and translational findings. To advance mitochondrial discoveries into clinical practice, subsequent studies must prioritize achieving spatiotemporally controlled, cell-type-specific interventions with robust in vivo efficacy, thereby successfully translating mitochondrial science into clinical vascular medicine.

Keywords:  diabetic retinopathy; inner blood-retinal barrier; mitochondrial dysfunction; mitochondrial plasticity; mitochondrial therapy; mitophagy; oxidative stress; retinal vein occlusion

DOI:  https://doi.org/10.3390/ijms262411984
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2508911123

Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.

Isidora Molina-Riquelme, Gonzalo Barrientos, Leonhard Breitsprecher, Wileidy Gómez, Francisco Díaz-Castro, Silke Morris, Gonzalo Almarza, Andrea Del Campo, Luis Garrido-Olivares, Hugo E Verdejo, Olympia Ekaterini Psathaki, Karin B Busch, Verónica Eisner.

  Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide. Mitochondrial dysfunction is a hallmark of cardiovascular aging. Most of the heart's ATP is produced at the cristae, specialized subcompartments where oxidative phosphorylation (OXPHOS) takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and ultrastructural alterations of cristae in human and mouse hearts. We found that aged patients' hearts displayed reduced cristae density as seen by transmission electron microscopy (TEM), even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multiscale approach that included TEM and serial block-face scanning electron microscopy (SBF-SEM) showed that in aged mice's hearts, cristae undergo ultrastructural remodeling processes, resulting in a decrease in cristae density and width. Electron tomography suggests an apparent decline in cristae connectivity and an increase in fenestration size. These changes were linked to Opa1 downregulation, accompanied by reduced maximal OXPHOS respiration, but unrelated to alterations in the abundance of OXPHOS core subunits and ATP synthase assembly. Altogether, this indicates that alterations in cristae structure alone are sufficient to impair oxidative metabolism, which highlights its potential as an early signal of cardiac aging, even before noticeable changes in mitochondrial morphology occur.

Keywords:  Opa1; aging; cristae; heart; mitochondria

DOI:  https://doi.org/10.1073/pnas.2508911123
Respir Res. 2025 Dec 28.

Mitochondrial quality control mechanisms as molecular targets for impaired lung development: from fetuses to neonates.

Ziwei Zhu, Liang Zhang, Jianhua Fu.



Keywords:  Bronchopulmonary dysplasia; Lung development; Mitochondrial homeostasis; Mitochondrial quality control

DOI:  https://doi.org/10.1186/s12931-025-03468-3
Int J Mol Sci. 2025 Dec 10. pii: 11907. [Epub ahead of print]26(24):

Disturbances in Mitochondrial Network, Biogenesis, and Mitochondria-Mediated Inflammatory Responses in Selected Brain Structures of Rats Exposed to Lead (Pb) During Prenatal and Neonatal Development.

Mikołaj Chlubek, Magdalena Gąssowska-Dobrowolska, Agnieszka Kolasa, Maciej Tarnowski, Patrycja Tomasiak, Agnieszka Maruszewska, Katarzyna Barczak, Irena Baranowska-Bosiacka.

  Lead (Pb) disrupts mitochondrial function, but its impact on the mitochondrial dynamics and biogenesis during early brain development remains insufficiently understood. This study aimed to investigate the effects of pre- and neonatal Pb exposure on the processes involved in mitochondrial network formation in the brains of rat offspring, simulating environmental exposure. We quantified mRNA expression (qRT-PCR) and protein levels (ELISA) of key mitochondrial fusion (Mfn1, Mfn2, Opa1), fission (Drp1, Fis1) regulators, as well as biogenesis markers (PGC-1α, TFAM, NRF1) in the hippocampus, forebrain cortex, and cerebellum of rats exposed to Pb. Mitochondrial ultrastructure was evaluated using transmission electron microscopy (TEM), and the expression of mitochondrial electron transport chain (ETC) genes was analysed (qRT-PCR). Furthermore, to examine the involvement of the cGAS-STING pathway in Pb-induced neuroinflammation, we measured the expression of ISGs (qRT-PCR), TBK1 phosphorylation (Western blot), and 2',3'-cGAMP synthesis (ELISA). Our results showed that Pb exposure markedly reduced PGC-1α and region-specific NRF1 levels, broadly supressed fusion proteins (Mfn1, Mfn2, Opa1), increased Fis1, and depleted Drp1. ETC gene expression (mtNd1, mtCyb and mtCo1) were upregulated in a brain-structure-dependent manner. These molecular changes were accompanied by pronounced mitochondrial morphological abnormalities. Despite upregulation of Mx1, Ifi44, and Sting1, along with synthesis of 2'3'-cGAMP, TBK1 activation was not detected. All these findings demonstrate that early-life Pb exposure, even low-dose, disrupts mitochondrial biogenesis and the fusion-fission machinery, thus impairs brain energy homeostasis, and implicates mitochondria as central mediators of Pb-induced neuroinflammation and neurodevelopmental toxicity.

Keywords:  cGAS-STING pathway; developmental lead exposure; lead neurotoxicity; mitochondrial biogenesis; mitochondrial fission/fusion; rat brain

DOI:  https://doi.org/10.3390/ijms262411907
Cell Death Dis. 2025 Dec 27.

Prime editing links the split integrated stress response to pathogenic eIF2B mutations and white matter degeneration.

Alessandra Scagliola, Annarita Miluzio, Martina Pauselli, Marcello Ceci, Stefano Biffo, Sara Ricciardi.

Vanishing White Matter Disease (VWMD) is a devastating, currently incurable neurodevelopmental disorder primarily affecting white matter. The prevailing view attributes VWMD to the activation of the canonical integrated stress response (c-ISR). However, recent studies have identified a novel, distinct pathway called the split ISR (s-ISR), though its activation has so far only been documented in mouse stem cells harboring a single eIF2B mutation, leaving uncertainty about whether it occurs in human cells, whether other mutations can trigger it, and what role it plays in the disease. Here, we used prime editing (PE) to engineer multiple eIF2B pathogenic mutations into HEK293T and induced pluripotent stem cells (iPSCs), generating human models. We demonstrated PE's effectiveness and safety, marking the first successful application of PE for modeling VWMD. We found that all modeled mutations activate the s-ISR, indicating that this response is a common feature across VWMD mutations, and that it can be further amplified by stress-induced c-ISR and effectively suppressed by ISRIB. Mechanistically, we show that s-ISR hinders mutant iPSCs from achieving the high protein synthesis levels necessary for proper differentiation, expecially into astrocytes. This impairment disrupts their maturation process, directly linking s-ISR activation to the white matter abnormalities of VWMD.

DOI: https://doi.org/10.1038/s41419-025-08399-x
Neurobiol Dis. 2025 Dec 30. pii: S0969-9961(25)00472-3. [Epub ahead of print] 107255

Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts.

Barbara Pakula, Agata Wydrych, Magdalena Lebiedzinska-Arciszewska, Patrycja Jakubek-Olszewska, Marta Skowrońska, Iwona Kurkowska-Jastrzębska, Justyna Janikiewicz, Aneta M Dobosz, Emre Hakli, Jędrzej Szymański, Paolo Pinton, Agnieszka Dobrzyń, Werner J H Koopman, Mariusz R Wieckowski.

  Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) is the third most common genetically-defined subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), a group of rare, clinically heterogeneous disorders. The MPAN pathomechanism, including the link between C19orf12 mutations, iron accumulation, and metabolic alterations, is still poorly understood. While earlier research pointed to impaired autophagy in MPAN, a comprehensive understanding remains elusive. Here, we investigated the autophagy-linked proteome in primary fibroblasts derived from 18 MPAN patients and identified distinct alterations in autophagy-related protein expression. Importantly, a subset of these proteomic changes showed significant associations with disease severity, highlighting their potential relevance as biomarkers of clinical progression. Functional analyses further revealed increased lysosomal acidification as the most consistently affected autophagy-related process in MPAN fibroblasts. Notably, both proteomic and functional alterations were associated with C19orf12 mutation zygosity, underscoring its modulatory role in disease-relevant cellular pathways.

Keywords:  Autophagy flux; Ferrous iron; Fibroblasts; Lysosomal pH; Mitochondrial membrane protein-associated neurodegeneration; Proteomic analysis; V-ATPase

DOI:  https://doi.org/10.1016/j.nbd.2025.107255
Nat Neurosci. 2025 Dec 29.

Fractal analysis of brain shape formation predicts age and genetic similarity in human newborns.

Stephan Krohn, Amy Romanello, Nina von Schwanenflug, Jerod M Rasmussen, Claudia Buss, Sofie L Valk, Christopher R Madan, Carsten Finke.

The neonatal period represents a critical phase of human brain development. During this time, the brain shows a dramatic increase in size, but how its morphology emerges in early life remains largely unknown. Here we show that human newborns undergo a rapid formation of brain shape, beyond the expected growth in brain size. Using fractal dimensionality (FD) analysis of structural neuroimaging data, we show that brain shape strongly reflects infant maturity beyond differences in brain size, significantly outperforms brain size in predicting infant age at scan (mean error approximately 4 days), detects signatures of premature birth that are not captured by brain size, is systematically more sensitive to genetic variability among infants and is superior in predicting which newborns are twin siblings, with up to 97% accuracy. Additionally, FD captures age and genetic information significantly better than earlier morphological measures, including cortical thickness, curvature, gyrification, sulcation, surface area and the T1-weighted/T2-weighted ratio. These findings identify the formation of brain shape as a fundamental maturational process in human brain development and show that, biologically, FD should be interpreted as a developmental marker of early-life brain maturity, which is rooted in geometry rather than size.

DOI: https://doi.org/10.1038/s41593-025-02107-w
Cell Biosci. 2025 Dec 27.

PGC-1α: key regulator of mitochondrial biogenesis and cellular differentiation in metabolic and regenerative tissues.

Lijuan Cao, Yanan Li, Artem Smirnov, Ramouna Voshtani, Tingting Wang, Changshun Shao, Eleonora Candi, Gerry Melino, Yufang Shi, Jiankai Fang.

  Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a crucial coactivator that regulates mitochondrial biogenesis and function across diverse tissues, including the brain, heart, skeletal muscle, bone marrow, and liver. The diversity of PGC-1α isoforms in distinct tissues allows this co-transcription factor to exert wide-ranging biological effects, including regulating mitochondrial functions, oxidative stress, and endoplasmic reticulum homeostasis. Here, we focus on the key roles of PGC-1α in cell differentiation. Initially identified in brown adipose tissue in response to cold exposure, PGC-1α regulates cell differentiation by modulating gene expression networks involved in mitochondrial biogenesis. PGC-1α influences cell fate in several cell types, including adipocytes, skeletal muscle cells, and bone marrow-derived cells. A deeper understanding of PGC-1α provides valuable insights into developmental biology, tissue formation, and potential therapeutic targets for regenerative medicine and disease treatment. This review explores recent progress in understanding the roles of PGC-1α in cell differentiation, offering an integrated perspective on its significance in tissue and organism development.

Keywords:  Cell differentiation; Metabolic reprogramming; PGC-1α; Tissue regeneration

DOI:  https://doi.org/10.1186/s13578-025-01519-2