bims-mitmed 2024-12-22 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–12–22
thirty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
Mapping mitochondrial aging.
Aged neurons don't register energy need.
Updates on neurologic manifestations of mitochondrial disease.
Proteolytic regulation of mitochondrial magnesium channel MRS2 by m-AAA protease and prohibitin complex.
Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.
NDUFAF5 variants cause early onset Leigh syndrome.
A molecular glue for Prkn/parkin.
Mitochondrial dysfunction has a central role in diabetic kidney disease.
Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.
Dynamic mitophagy trajectories hallmark brain aging.
Novel PNPLA8 variants associated with primary ovarian insufficiency, tremors, cerebellar ataxia and limb weakness: a case report and literature review.
Metformin targets mitochondrial complex I to lower blood glucose levels.
Aging promotes an increase in mitochondrial fragmentation in astrocytes.
Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities.
Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
Mitochondrial DNA Damage and Its Repair Mechanisms in Aging Oocytes.
Mitochondrial Transplantation Ameliorates Pulmonary Fibrosis by Suppressing Myofibroblast Activation.
Lithocholic acid phenocopies anti-ageing effects of calorie restriction.
Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in charcot-marie-tooth type 2 neuropathies.
Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
A Kinetic Model for Compound Heterozygous Pathogenic Variants in Tyrosyl-tRNA Synthetase Gene YARS2-Associated Neonatal Phenotype.
Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.
Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.
Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening through MFN1.
Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.
Advances in Osteoblast and Mitochondrial Dynamics and Their Transfer in Osteoporosis.
A family of NADPH/NADP+ biosensors reveals in vivo dynamics of central redox metabolism across eukaryotes.

Nat Metab. 2024 Dec;6(12): 2319-2337

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.

Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.

The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.

DOI: https://doi.org/10.1038/s42255-024-01174-w
Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13

Mapping mitochondrial aging.

Alessandro Bitto.

  Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.105191
Science. 2024 Dec 20. 386(6728): 1349-1350

Aged neurons don't register energy need.

Deniz Bingul, Scott F Owen.

Neuronal activity and mitochondrial gene expression become decoupled in aged mice.

DOI: https://doi.org/10.1126/science.adu4935
Curr Opin Pediatr. 2025 Feb 01. 37(1): 107-111

Updates on neurologic manifestations of mitochondrial disease.

Britta Kuusik, Divakar S Mithal.

PURPOSE OF REVIEW: Primary mitochondrial disease (PMD) is diverse both genetically and phenotypically. Neurologic manifestations are present at a high rate and often pose complications for providers. The review will discuss common manifestations and how advances in genetic testing have broadened understanding of PMDs.
RECENT FINDINGS: Across all areas of PMD research, genetic advancements are notable both for mitochondrial and nuclear DNA.
SUMMARY: Global understanding of PMDs is driving deeper and broader research. Neurologic manifestations primarily include neuromuscular disease, epilepsy, stroke-like episodes and neurodegeneration, and advances in all areas have benefitted from global reporting of genetic studies.

DOI: https://doi.org/10.1097/MOP.0000000000001418
Genetics. 2024 Dec 05. pii: iyae203. [Epub ahead of print]

Proteolytic regulation of mitochondrial magnesium channel MRS2 by m-AAA protease and prohibitin complex.

Alaumy Joshi, Rachel A Stanfield, Andrew T Spletter, Vishal M Gohil.

  Mitochondrial membrane phospholipid cardiolipin is essential for the stability of several inner mitochondrial membrane protein complexes. We recently showed that the abundance of mitochondrial magnesium channel MRS2 is reduced in models of Barth syndrome, an X-linked genetic disorder caused by a remodeling defect in cardiolipin. However, the mechanism underlying the reduced abundance of MRS2 in cardiolipin-depleted mitochondria remained unknown. In this study, we utilized yeast mutants of mitochondrial proteases to identify an evolutionarily conserved m-AAA protease, Yta10/Yta12, responsible for degrading Mrs2. The activity of m-AAA protease is regulated by the inner mitochondrial membrane scaffolding complex prohibitin, and consistent with this role, we find that Mrs2 turnover is increased in yeast prohibitin mutants. Importantly, we find that deleting Yta10 in cardiolipin-deficient yeast cells restores the steady-state levels of Mrs2 to the wild-type cells, and the knockdown of AFG3L2, a mammalian homolog of Yta12, increases the abundance of MRS2 in a murine muscle cell line. Thus, our work has identified the m-AAA protease/prohibitin complex as an evolutionarily conserved regulator of Mrs2 that can be targeted to restore Mrs2 abundance in cardiolipin-depleted cells.

Keywords:   m-AAA protease; MRS2; Mitochondria; cardiolipin; prohibitin

DOI:  https://doi.org/10.1093/genetics/iyae203
Annu Rev Physiol. 2024 Dec 10.

Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?

David J Bishop, Matthew J-C Lee, Martin Picard.

Mitochondria are multifaceted organelles with several life-sustaining functions beyond energy transformation, including cell signaling, calcium homeostasis, hormone synthesis, programmed cell death (apoptosis), and others. A defining aspect of these dynamic organelles is their remarkable plasticity, which allows them to sense, respond, and adapt to various stressors. In particular, it is well-established that the stress of exercise provides a powerful stimulus that can trigger transient or enduring changes to mitochondrial molecular features, activities, integrated functions, behaviors, and cell-dependent mitochondrial phenotypes. Evidence documenting the many beneficial mitochondrial adaptations to exercise has led to the notion of exercise as a mitochondrial medicine. However, as with other medicines, it is important to understand the optimal prescription (i.e., type, dose, frequency, duration). In this review, we build on a systematic biological framework that distinguishes between domains of mitochondrial biology to critically evaluate how different exercise prescription variables influence mitochondrial adaptations to training.

DOI: https://doi.org/10.1146/annurev-physiol-022724-104836
Cell Mol Biol Lett. 2024 Dec 18. 29(1): 153

Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.

Meng Zhang, Jin Wei, Chang He, Liutao Sui, Chucheng Jiao, Xiaoyan Zhu, Xudong Pan.

  Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Keywords:  Age-related diseases; Aging; Mitochondrial communication; Mitochondrial dysfunction; Signaling hubs

DOI:  https://doi.org/10.1186/s11658-024-00669-4
Aging Cell. 2024 Dec 16. e14402

Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.

Amy R Vandiver, Alejandro Torres, Amberly Sanden, Thang L Nguyen, Jasmine Gasilla, Mary T Doan, Vahan Martirosian, Austin Hoang, Jonathan Wanagat, Michael A Teitell.

  The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.

Keywords:  aging; iPSC; mitochondria; mtDNA mutation

DOI:  https://doi.org/10.1111/acel.14402
Front Mol Neurosci. 2024 ;17 1504802

Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.

Michael Aschner, Anatoly V Skalny, Rongzhu Lu, Airton C Martins, Yousef Tizabi, Sergey V Nekhoroshev, Abel Santamaria, Anton I Sinitskiy, Alexey A Tinkov.

  Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Keywords:  copper; cuproptosis; fission; mitochondrial fusion; mitophagy

DOI:  https://doi.org/10.3389/fnmol.2024.1504802
Parkinsonism Relat Disord. 2024 Dec 09. pii: S1353-8020(24)01239-2. [Epub ahead of print]131 107227

NDUFAF5 variants cause early onset Leigh syndrome.

Breno Kazuo Massuyama, Amanda Monteiro Viagi, Rafael Chaves Claudino de Queiroga, Raphael Pinheiro Camurugy da Hora, Victor Rebelo Procaci, Augusto Bragança Reis Rosa, Thiago Yoshinaga Tonholo Silva, Orlando Graziani Povoas Barsottini, José Luiz Pedroso.



Keywords:  Leigh disease; Mitochondrial diseases; NDUFAF5

DOI:  https://doi.org/10.1016/j.parkreldis.2024.107227
Autophagy. 2024 Dec 19.

A molecular glue for Prkn/parkin.

Véronique Sauvé, Kalle Gehring.

  Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra, primarily due to mitochondria dysfunction. PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN induced kinase 1) are linked to early-onset cases of PD and essential for the clearance of damaged mitochondria via selective mitochondrial autophagy (mitophagy). In a recent publication, we detail how a small molecule can activate PRKN mutants that are unable to be phosphorylated, restoring mitophagy in cellular assays. These findings offer hope for the design of therapeutic drugs for some forms of PD.

Keywords:  Activator; PARK2; mitochondria; neurodegeneration; parkinson disease; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2024.2443232
Nat Rev Nephrol. 2024 Dec 16.

Mitochondrial dysfunction has a central role in diabetic kidney disease.

Shen Li, Katalin Susztak.

DOI: https://doi.org/10.1038/s41581-024-00919-w
Life Sci. 2024 Dec 12. pii: S0024-3205(24)00907-X. [Epub ahead of print] 123317

Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.

Mengnan Liu, Binru Li, Zhixue Yin, Lu Yin, Ye Luo, Qi Zeng, Dechou Zhang, Anguo Wu, Li Chen.

  Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.

Keywords:  Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Neuroprotection strategies; Secondary brain injury

DOI:  https://doi.org/10.1016/j.lfs.2024.123317
Autophagy. 2024 Dec 19. 1-3

Dynamic mitophagy trajectories hallmark brain aging.

Anna Rappe, Thomas G McWilliams.

  Studies using mitophagy reporter mice have established steady-state landscapes of mitochondrial destruction in mammalian tissues, sparking intense interest in basal mitophagy. Yet how basal mitophagy is modified by healthy aging in diverse brain cell types has remained a mystery. We present a comprehensive spatiotemporal analysis of mitophagy and macroautophagy dynamics in the aging mammalian brain, reporting critical region- and cell-specific turnover trajectories in a longitudinal study. We demonstrate that the physiological regulation of mitophagy in the mammalian brain is cell-specific, dynamic and complex. Mitophagy increases significantly in the cerebellum and hippocampus during midlife, while remaining unchanged in the prefrontal cortex (PFC). Conversely, macroautophagy decreases in the hippocampus and PFC, but remains stable in the cerebellum. We also describe emergent lysosomal heterogeneity, with subsets of differential acidified lysosomes accumulating in the aging brain. We further establish midlife as a critical inflection point for autophagy regulation, which may be important for region-specific vulnerability and resilience to aging. By mapping in vivo autophagy dynamics at the single cell level within projection neurons, interneurons and microglia, to astrocytes and secretory cells, we provide a new framework for understanding brain aging and offer potential targets and timepoints for further study and intervention in neurodegenerative diseases.

Keywords:  Aging; autophagy; brain; mitochondria; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2426115
J Neurol. 2024 Dec 16. 272(1): 78

Novel PNPLA8 variants associated with primary ovarian insufficiency, tremors, cerebellar ataxia and limb weakness: a case report and literature review.

Bin Chen, Cuiping Zhang, Yun Yuan, Zhan Wang, Tao Cui, Gehong Dong, Hua Pan, Zaiqiang Zhang, Wei Li.

   BACKGROUND: PNPLA8 is a gene that causes an autosomal recessive mitochondrial disease characterised by microcephaly and intractable epilepsy in infants and cerebellar ataxia and limb weakness in adults. Herein, we report the clinical, muscle pathology, and brain imaging features of an adult patient with new variants of PNPLA8.
METHODS: A 27-year-old Chinese woman presented with abnormal gait at age 11, remained amenorrhoeic with an infantile uterus at age 17, and presented with head and limb tremors at age 21. The results of brain magnetic resonance imaging suggested mild cerebellar atrophy. Whole-exome sequencing was performed, and mitochondrial and spinal cerebellar ataxia genes were screened. In addition, a biceps muscle biopsy was performed. Furthermore, a comprehensive literature search was conducted, and all patients with detailed clinical and genetic data up to October 2024 were included in the analysis.
RESULTS: The patient's genetic screening revealed compound heterozygous variants c.1777T > G (p.Tyr593Asp) and c.1515-1516delTT (p.Tyr506Serfs*27) of PNPLA8 inherited from her parents. Her muscle biopsy showed mild myopathic changes on light microscopy and mitochondrial inclusions on electron microscopy. A total of 25 patients from 21 families were reviewed.
CONCLUSION: Age of onset is a very important factor in terms of patient clinical phenotype and prognosis of PNPLA8-related disorders. It has been observed that adult females with PNPLA8 variants may present with primary ovarian dysfunction. The presence of mitochondrial inclusion bodies may serve as a pathological hallmark, extending the existing spectrum of the clinical phenotypes and pathogenic variants of PNPLA8.

Keywords:   PNPLA8 ; Ataxia; Microcephaly; Mitochondrial inclusions; Primary ovarian insufficiency

DOI:  https://doi.org/10.1007/s00415-024-12838-8
Sci Adv. 2024 Dec 20. 10(51): eads5466

Metformin targets mitochondrial complex I to lower blood glucose levels.

Colleen R Reczek, Ram P Chakrabarty, Karis B D'Alessandro, Zachary L Sebo, Rogan A Grant, Peng Gao, G R Budinger, Navdeep S Chandel.

Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.

DOI: https://doi.org/10.1126/sciadv.ads5466
Front Cell Neurosci. 2024 ;18 1496163

Aging promotes an increase in mitochondrial fragmentation in astrocytes.

Ana Paula Bergamo Araujo, Gabriele Vargas, Lívia de Sá Hayashide, Isadora Matias, Cherley Borba Vieira Andrade, Jorge José de Carvalho, Flávia Carvalho Alcantara Gomes, Luan Pereira Diniz.

   Introduction: Brain aging involves a complex interplay of cellular and molecular changes, including metabolic alterations and the accumulation of senescent cells. These changes frequently manifest as dysregulation in glucose metabolism and mitochondrial function, leading to reduced energy production, increased oxidative stress, and mitochondrial dysfunction-key contributors to age-related neurodegenerative diseases.
Methods: We conducted experiments on two models: young (3-4 months) and aged (over 18 months) mice, as well as cultures of senescent and control mouse astrocytes. Mitochondrial content and biogenesis were analyzed in astrocytes and neurons from aged and young animals. Cultured senescent astrocytes were examined for mitochondrial membrane potential and fragmentation. Quantitative PCR (qPCR) and immunocytochemistry were used to measure fusion- and fission-related protein levels. Additionally, transmission electron microscopy provided morphological data on mitochondria.
Results: Astrocytes and neurons from aged animals showed a significant reduction in mitochondrial content and a decrease in mitochondrial biogenesis. Senescent astrocytes in culture exhibited lower mitochondrial membrane potential and increased mitochondrial fragmentation. qPCR and immunocytochemistry analyses revealed a 68% increase in fusion-related proteins (mitofusin 1 and 2) and a 10-fold rise in DRP1, a key regulator of mitochondrial fission. Transmission electron microscopy showed reduced perimeter, area, and length-to-diameter ratio of mitochondria in astrocytes from aged mice, supported by elevated DRP1 phosphorylation in astrocytes of the cerebral cortex.
Discussion: Our findings provide novel evidence of increased mitochondrial fragmentation in astrocytes from aged animals. This study sheds light on mechanisms of astrocytic metabolic dysfunction and mitochondrial dysregulation in brain aging, highlighting mitochondrial fragmentation as a potential target for therapeutic interventions in age-related neurodegenerative diseases.

Keywords:  astrocytes; brain aging; mitochondrial biogenesis and neurodegeneration; mitochondrial dysfunction; mitochondrial fragmentation

DOI:  https://doi.org/10.3389/fncel.2024.1496163
Curr Opin Neurol. 2024 Dec 23.

Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities.

Benson S Chen, Nancy J Newman.

PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disease characterised by sequential bilateral vision loss due to loss of retinal ganglion cells. The purpose of this review is to provide an update on the results of recent clinical trials for LHON, focusing on studies of idebenone and lenadogene nolparvovec gene therapy.
RECENT FINDINGS: Evidence from three clinical studies (RHODOS, RHODOS-OFU, and LEROS) suggest that idebenone should be started early and continued for at least 24 months. Treatment effect varies according to the stage of LHON and the underlying mutation. Favourable outcomes are associated with the m.11778G>A mutation and chronic eyes with the m.14484T>C mutation. Caution should be taken in subacute/dynamic eyes with the m.3460G>A mutation, due to possible clinical worsening with idebenone. Compared to eyes from an external natural history cohort, pooled data from four clinical studies (RESCUE, REVERSE, RESTORE and REFLECT) show that a single intravitreal injection of lenadogene nolparvovec can result in sustained bilateral visual improvement in m.11778G>A LHON patients aged ≥15 years when treated within 1 year of onset. Although the treatment effect is modest, the final visual acuity of treated patients (∼1.2 logMAR) significantly differs from the published natural history of LHON and the treatment benefit is more pronounced than the effect of idebenone alone in patients with the m.11778G>A mutation.
SUMMARY: There is increasing evidence for the potential therapeutic benefit of idebenone and lenadogene nolparvovec gene therapy.

DOI: https://doi.org/10.1097/WCO.0000000000001343
Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]

Mitochondrial metabolism and epigenetic crosstalk drive the SASP.

Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams.

Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

DOI: https://doi.org/10.21203/rs.3.rs-5278203/v1
Autophagy. 2024 Dec 15.

Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.

Isabel Gordaliza-Alaguero, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Laura Villarreal, Gianluca Arauz-Garofalo, Marina Gay, Marta Martinez-Vicente, Jorge Seco, Pau Martin-Malpartida, Marta Vilaseca, María J Macías, Manuel Palacin, Saška Ivanova, Antonio Zorzano.

  MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA. HA-affinity isolation followed by mass spectrometry identified potential interactors of MFN1 and MFN2. A substantial proportion of interactors were common for MFN1 and MFN2 and were regulated by nutrient deprivation. We validated novel ER and endosomal partners of MFN1 and/or MFN2 with a potential role in interorganelle communication. We characterized RAB5C (RAB5C, member RAS oncogene family) as an endosomal modulator of mitochondrial homeostasis, and SLC27A2 (solute carrier family 27 (fatty acid transporter), member 2) as a novel partner of MFN2 relevant in autophagy. We conclude that MFN proteins participate in nutrient-modulated pathways involved in organelle communication and autophagy.

Keywords:  Autophagosomes; endosomes; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; nutrient deprivation

DOI:  https://doi.org/10.1080/15548627.2024.2440843
Int J Mol Sci. 2024 Dec 06. pii: 13144. [Epub ahead of print]25(23):

Mitochondrial DNA Damage and Its Repair Mechanisms in Aging Oocytes.

Hiroshi Kobayashi, Shogo Imanaka.

  The efficacy of assisted reproductive technologies (ARTs) in older women remains constrained, largely due to an incomplete understanding of the underlying pathophysiology. This review aims to consolidate the current knowledge on age-associated mitochondrial alterations and their implications for ovarian aging, with an emphasis on the causes of mitochondrial DNA (mtDNA) mutations, their repair mechanisms, and future therapeutic directions. Relevant articles published up to 30 September 2024 were identified through a systematic search of electronic databases. The free radical theory proposes that reactive oxygen species (ROS) inflict damage on mtDNA and impair mitochondrial function essential for ATP generation in oocytes. Oocytes face prolonged pressure to repair mtDNA mutations, persisting for up to five decades. MtDNA exhibits limited capacity for double-strand break repair, heavily depending on poly ADP-ribose polymerase 1 (PARP1)-mediated repair of single-strand breaks. This process depletes nicotinamide adenine dinucleotide (NAD⁺) and ATP, creating a detrimental cycle where continued mtDNA repair further compromises oocyte functionality. Interventions that interrupt this destructive cycle may offer preventive benefits. In conclusion, the cumulative burden of mtDNA mutations and repair demands can lead to ATP depletion and elevate the risk of aneuploidy, ultimately contributing to ART failure in older women.

Keywords:  aging oocytes; mitochondrial DNA (mtDNA); mtDNA mutations; nicotinamide adenine dinucleotide; poly ADP-ribose polymerase 1 (PARP1)

DOI:  https://doi.org/10.3390/ijms252313144
Int J Mol Sci. 2024 Nov 28. pii: 12783. [Epub ahead of print]25(23):

Mitochondrial Transplantation Ameliorates Pulmonary Fibrosis by Suppressing Myofibroblast Activation.

Seo-Eun Lee, Shin-Hye Yu, In-Hyeon Kim, Young Cheol Kang, Yujin Kim, Jeong Seon Yeo, Jun Hyeok Lim, Iksun Kwon, Je-Hein Kim, Se-Woong Park, Mi-Yoon Chang, Kyuboem Han, Sung-Hwan Kim, Chun-Hyung Kim.

  Idiopathic pulmonary fibrosis (IPF) is a pulmonary disease characterized by excessive extracellular matrix protein deposition in the lung interstitium, subsequently causing respiratory failure. IPF still has a high medical unmet requirement due to the lack of effective treatments to inhibit disease progression. The etiology of IPF remains unclear, but mitochondrial dysfunction is considered to be associated with IPF development. Therefore, targeting mitochondrial abnormalities would be a promising strategy for treating IPF. Recently, exogenous mitochondrial transplantation has been beneficial for treating mitochondrial dysfunction. The current study aimed to examine the therapeutic effect of mitochondrial transplantation on IPF in vitro and in vivo. Mitochondria were isolated from human umbilical cord mesenchymal stem cells, referred to as PN-101. Human lung fibroblasts and human bronchial epithelial cells were exposed to transforming growth factor-β, followed by PN-101 treatment to determine the in vitro efficacy of mitochondrial transplantation. An IPF mouse model established by a single intratracheal instillation of bleomycin was utilized to determine the in vivo efficacy of the intravenously treated mitochondria. PN-101 attenuated mitochondrial damage, inhibited EMC production, and suppressed epithelial-to-mesenchymal transition in vitro. Additionally, intravenous PN-101 administration alleviated bleomycin-induced fibrotic processes in the IPF mouse model with a therapeutic context. Our data indicate that PN-101 is a novel and potential therapeutic agent for IPF.

Keywords:  anti-inflammation; antiapoptosis; idiopathic pulmonary fibrosis (IPF); mitochondria; stem cell; transplantation

DOI:  https://doi.org/10.3390/ijms252312783
Nature. 2024 Dec 18.

Lithocholic acid phenocopies anti-ageing effects of calorie restriction.

Qi Qu, Yan Chen, Yu Wang, Shating Long, Weiche Wang, Heng-Ye Yang, Mengqi Li, Xiao Tian, Xiaoyan Wei, Yan-Hui Liu, Shengrong Xu, Cixiong Zhang, Mingxia Zhu, Sin Man Lam, Jianfeng Wu, Chuyu Yun, Junjie Chen, Shengye Xue, Baoding Zhang, Zhong-Zheng Zheng, Hai-Long Piao, Changtao Jiang, Hao Guo, Guanghou Shui, Xianming Deng, Chen-Song Zhang, Sheng-Cai Lin.

Calorie restriction (CR) is a dietary intervention used to promote health and longevity1,2. CR causes various metabolic changes in both the production and the circulation of metabolites1; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that alone can recapitulate the effects of CR in mice. These effects include activation of AMP-activated protein kinase (AMPK), enhancement of muscle regeneration and rejuvenation of grip strength and running capacity. LCA also activates AMPK and induces life-extending and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster. As C. elegans and D. melanogaster are not able to synthesize LCA, these results indicate that these animals are able to transmit the signalling effects of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes in all the three animal models. Together, we identify that administration of the CR-mediated upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans in an AMPK-dependent manner.

DOI: https://doi.org/10.1038/s41586-024-08329-5
Autophagy. 2024 Dec 19.

Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in charcot-marie-tooth type 2 neuropathies.

Angela Sisto, Tamira van Wermeskerken, Michael Pancher, Pamela Gatto, Bob Asselbergh, Ágata Sofia Assunção Carreira, Vicky De Winter, Valentina Adami, Alessandro Provenzani, Vincent Timmerman.

  HSPB1 [heat shock protein family B (small) member 1] and HSPB8 are essential molecular chaperones for neuronal proteostasis, as they prevent protein aggregation. Mutant HSPB1 and HSPB8 primarily harm peripheral neurons, resulting in axonal Charcot-Marie-Tooth neuropathies (CMT2). Macroautophagy/autophagy is a shared mechanism by which HSPB1 and HSPB8 mutations cause neuronal dysfunction. Autophagosome formation is reduced in mutant HSPB1-induced pluripotent stem-cell-derived motor neurons from CMT type 2F patients. Likewise, the HSPB8K141N knockin mouse model, mimicking CMT type 2 L, exhibits axonal degeneration and muscle atrophy, with SQSTM1/p62-positive deposits. We show here that mouse embryonic fibroblasts isolated from a HSPB8K141N/green fluorescent protein (GFP)-LC3 model have diminished autophagosome production under conditions of MTOR inhibition. To correct the autophagic deficits in the HSPB1 and HSPB8 models, we screened by high-throughput autophagosome quantification the repurposing Spectrum Collection library for molecules that could boost the autophagic activity above the canonical MTOR inhibition. Hit compounds were validated on motor neurons obtained by differentiation of HSPB1P182L and HSPB8K141N patient-derived induced pluripotent stem cells, focusing on autophagy induction as well as neurite network density, axonal degeneration, and mitochondrial morphology. We identified molecules that specifically stimulate autophagosome formation in the HSPB8K141N cells, without affecting autophagy flux. Two top lead compounds induced autophagy and reduced axonal degeneration, thus promoting neuronal network maturation in the CMT2 patient-derived motor neurons. Based on these findings, the phenotypical screen revealed that piplartine rescued autophagy deficiencies in both the HSPB1 and HSPB8 models, demonstrating autophagy induction as an effective therapeutic strategy for CMT neuropathies and other chaperonopathies.

Keywords:  Autophagy inducer; drug repurposing; inherited peripheral neuropathy; motor neurons; phenotypical screening; small heat shock proteins

DOI:  https://doi.org/10.1080/15548627.2024.2439649
Nat Metab. 2024 Dec;6(12): 2215-2217

Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.

Fiona M Fitzpatrick, Nora Kory.

DOI: https://doi.org/10.1038/s42255-024-01160-2
J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02594-8. [Epub ahead of print] 108092

A Kinetic Model for Compound Heterozygous Pathogenic Variants in Tyrosyl-tRNA Synthetase Gene YARS2-Associated Neonatal Phenotype.

Thomas Christian, Sunita Maharjan, Sitao Yin, Yuka Yamaki, Isao Masuda, Fenglin Li, Colleen Muraresku, Sheila Clever, Rebecca D Ganetzky, Ya-Ming Hou.

  Human genetic disorders are often caused by mutations of compound heterozygosity, where each allele of the mutant gene harbors a different genetic lesion. However, studies of such mutations are hampered, due to the lack of an appropriate model. Here we describe a kinetic model of compound heterozygous variants in an obligate enzyme dimer that contains one mutation in one monomer and the other mutation in the second monomer. This enzyme is encoded by human YARS2 for mitochondrial tyrosyl-tRNA synthetase (mt-TyrRS), which aminoacylates tyrosine to mt-tRNATyr. YARS2 is a member of the genes for mt-aminoacyl-tRNA synthetases, where pathogenic mutations present limited correlation between disease severity and enzyme activity. We identify a pair of compound heterozygous variants in YARS2 that is associated with neonatal fatality. We show that, while each mutation causes a minor-to-modest defect in aminoacylation in the homodimer of mt-TyrRS, the two mutations in trans synergistically reduce the enzyme activity to a greater effect. This kinetic model thus accurately recapitulates the disease severity, emphasizing its utility to study YARS2 mutations and its potential for generalization to other diseases with compound heterozygous mutations.

Keywords:  MLASA; heterodimer; homodimer; mt-TyrRS; mt-tRNA(Tyr)

DOI:  https://doi.org/10.1016/j.jbc.2024.108092
JAMA Ophthalmol. 2024 Dec 19.

Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy.

LHON Study Group

Importance: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).
Objective: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.
Design, Setting, and Participants: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the MT-ND4 Mutation). At the end of each study, ie, 2 years after gene therapy administration, patients were offered enrollment in the RESTORE trial, a multinational, multicenter, prospective study, for an additional 3 years of follow-up. Patients with LHON due to the MT-ND4 gene variant received lenadogene nolparvovec in 1 eye and a sham injection in the other eye.
Intervention: Lenadogene nolparvovec was administered as a single intravitreal injection in the RESCUE/REVERSE studies.
Main Outcomes and Measures: Measures included best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25 (NEI VFQ-25), and adverse events.
Results: Among the 76 patients who received gene therapy in the RESCUE (n = 39) and REVERSE (n = 37) studies, 72 (94.7%) completed these studies; 62 patients (81.6%) participated in the RESTORE trial, and 55 patients (72.4%) completed the 5-year follow-up. Participants were mostly male (49 [79.0%]) with a mean (SD) age of 35.9 (15.3) years at treatment. At baseline, the mean (SD) BCVA was 1.5 (0.5) logMAR (20/600 Snellen) in eyes to be treated with lenadogene nolparvovec and 1.4 (0.5) logMAR (20/500) in sham eyes. At the end of the RESCUE/REVERSE trials, ie, 2 years after treatment, eyes treated with lenadogene nolparvovec and eyes treated with sham reached a mean BCVA value of 1.4 (0.6) logMAR (20/500). The mean (SD) change from baseline to year 2 was -0.05 (0.6) logMAR (+1 line) and 0.01 (0.6) logMAR (-0 line) in gene therapy-treated and sham eyes, respectively (difference, -0.03; 95% CI, -0.16 to 0.09; P = .60). Five years after treatment, the bilateral improvement from nadir was similar to that observed at 2 years, with a mean (SD) change in BCVA of -0.4 (0.5) logMAR (more than +4 lines) for eyes treated with lenadogene nolparvovec and -0.4 (0.4) logMAR (+4 lines) for eyes treated with sham (difference, -0.05; 95% CI, -0.15 to 0.04; P = .27). An improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least 1 eye was observed in 66.1% of participants (41 of 62). Between 2 and 5 years, intraocular inflammation was noted in 4 participants with 8 events in eyes treated with lenadogene nolparvovec and 1 event in an eye treated with sham.
Conclusions and Relevance: In this analysis of the RESTORE trial, follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients.
Trial Registration: ClinicalTrials.gov Identifier: NCT03406104.

DOI: https://doi.org/10.1001/jamaophthalmol.2024.5375
Nature. 2024 Dec 18.

Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.

Qi Qu, Yan Chen, Yu Wang, Weiche Wang, Shating Long, Heng-Ye Yang, Jianfeng Wu, Mengqi Li, Xiao Tian, Xiaoyan Wei, Yan-Hui Liu, Shengrong Xu, Jinye Xiong, Chunyan Yang, Zhenhua Wu, Xi Huang, Changchuan Xie, Yaying Wu, Zheni Xu, Cixiong Zhang, Baoding Zhang, Jin-Wei Feng, Junjie Chen, Yuanji Feng, Huapan Fang, Liyun Lin, Z K Xie, Beibei Sun, Huayu Tian, Yong Yu, Hai-Long Piao, Xiao-Song Xie, Xianming Deng, Chen-Song Zhang, Sheng-Cai Lin.

Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing1. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway. Proteomics analyses of proteins that co-immunoprecipitated with sirtuin 1 (SIRT1) identified TUB-like protein 3 (TULP3), a sirtuin-interacting protein2, as a LCA receptor. In detail, LCA-bound TULP3 allosterically activates sirtuins, which then deacetylate the V1E1 subunit of v-ATPase on residues K52, K99 and K191. Muscle-specific expression of a V1E1 mutant (3KR), which mimics the deacetylated state, strongly activates AMPK and rejuvenates muscles in aged mice. In nematodes and flies, LCA depends on the TULP3 homologues tub-1 and ktub, respectively, to activate AMPK and extend lifespan and healthspan. Our study demonstrates that activation of the TULP3-sirtuin-v-ATPase-AMPK pathway by LCA reproduces the benefits of calorie restriction.

DOI: https://doi.org/10.1038/s41586-024-08348-2
J Gerontol A Biol Sci Med Sci. 2024 Dec 19. pii: glae294. [Epub ahead of print]

Senolysis by GLS1 Inhibition Ameliorates Kidney Aging by Inducing Excessive mPTP Opening through MFN1.

Yuting Chen, Nan Zhao, Yu Zhang, Xueqi Chen, Yi Chen, Yifan Wang, Jianqing Wu, Weihong Zhao.

  Cellular senescence is a pivotal contributor to aging and age-related diseases. The targeted elimination of senescent cells, known as senolysis, has emerged as a promising therapeutic strategy for mitigating these conditions. Glutaminase 1 (GLS1), a key enzyme in the glutaminolysis pathway, has been implicated in various cellular senescence processes. However, its specific role in senescent renal tubular epithelial cells (TECs) remains unclear. This study investigates the role and underlying mechanisms of GLS1 in senescent TECs. Using D-galactose (D-gal)-induced senescence of HK-2 cells, we found that GLS1 inhibition eliminated senescent TECs by promoting excessive mitochondrial permeability transition pore (mPTP) opening. Mechanistically, the excessive mPTP opening is associated with upregulation of mitofusin 1 (MFN1). Inhibition of GLS1 in D-gal-treated HK-2 cells induced a shift in mitochondrial dynamics from fission to fusion, accompanied by a significant increase in MFN1 expression. Knocking down MFN1 reduced the mPTP opening and the expression of mPTP-related genes (PPIF, VDAC and BAX) in cells co-treated with D-gal and the GLS1 inhibitor BPTES. Moreover, treatment of aged mice with BPTES specifically eliminated senescent TECs and ameliorated age-associated kidney disease. These findings reveal that GLS1 inhibition eliminate senescent TECs by promoting excessive mPTP opening, suggesting that targeting GLS1 may be a novel senolytic strategy for alleviating aging-related kidney diseases.

Keywords:  GLS1; MFN1; kidney aging; mPTP; senolysis

DOI:  https://doi.org/10.1093/gerona/glae294
Science. 2024 Dec 20. 386(6728): eadp6547

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.

Wenwen Li, Jiarui Li, Jing Li, Chen Wei, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah Calubag, Lesley A Colgan, Kai Jin, Bing Zhou, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda, Huan Ma.

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TCmito), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TCnuc). We demonstrated that E-TCmito repurposes molecules traditionally associated with E-TCnuc to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TCmito weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TCmito in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.

DOI: https://doi.org/10.1126/science.adp6547
J Cell Mol Med. 2024 Dec;28(24): e70299

Advances in Osteoblast and Mitochondrial Dynamics and Their Transfer in Osteoporosis.

Jiaxuan Liu, Xuequan Zhang, Honghao Hou, Jun Ouyang, Jingxing Dai.

  Mitochondria are important organelles in the human body and play a major role in providing cellular energy, maintaining tissue homeostasis and apoptosis. Osteoporosis, characterised by a decrease in the amount of bone tissue per unit volume, is a metabolic bone pathology with multiple causes. Under pathological conditions, mitochondrial dysfunction leads to an imbalance in mitochondrial homeostasis, resulting in a disruption of osteoblast-osteoclast homeostasis, which in turn disrupts bone homeostasis, and this disruption of homeostasis is an important pathogenetic mechanism underlying chronic metabolic bone disease in osteoporosis. Numerous studies have shown that bone homeostasis is closely related to mitochondrial dynamics and mitochondrial translocation in the mitochondrial quality control system, and the balance between osteoblasts and osteoclasts is closely related to osteoporosis. In this review, we describe the progress of osteoblast and osteoclast research and mitochondrial dynamics in osteoporosis, and the role of mitochondrial translocation in bone homeostasis, in the hope that it can stimulate new research in osteoporotic metabolic bone disease and the development of novel therapeutic strategies.

Keywords:  mitochondrial dynamics; mitochondrial transfer; osteoblasts; osteoclasts; osteoporosis

DOI:  https://doi.org/10.1111/jcmm.70299
Nat Commun. 2024 Dec 19. 15(1): 10704

A family of NADPH/NADP+ biosensors reveals in vivo dynamics of central redox metabolism across eukaryotes.

Marie Scherschel, Jan-Ole Niemeier, Lianne J H C Jacobs, Markus D A Hoffmann, Anika Diederich, Christopher Bell, Pascal Höhne, Sonja Raetz, Johanna B Kroll, Janina Steinbeck, Sophie Lichtenauer, Jan Multhoff, Jannik Zimmermann, Tanmay Sadhanasatish, R Alexander Rothemann, Carsten Grashoff, Joris Messens, Emmanuel Ampofo, Matthias W Laschke, Jan Riemer, Leticia Prates Roma, Markus Schwarzländer, Bruce Morgan.

The NADPH/NADP+ redox couple is central to metabolism and redox signalling. NADP redox state is differentially regulated by distinct enzymatic machineries at the subcellular compartment level. Nonetheless, a detailed understanding of subcellular NADP redox dynamics is limited by the availability of appropriate tools. Here, we introduce NAPstars, a family of genetically encoded, fluorescent protein-based NADP redox state biosensors. NAPstars offer real-time, specific measurements, across a broad-range of NADP redox states, with subcellular resolution. NAPstar measurements in yeast, plants, and mammalian cell models, reveal a conserved robustness of cytosolic NADP redox homoeostasis. NAPstars uncover cell cycle-linked NADP redox oscillations in yeast and illumination- and hypoxia-dependent NADP redox changes in plant leaves. By applying NAPstars in combination with selective impairment of the glutathione and thioredoxin antioxidative pathways under acute oxidative challenge, we find an unexpected and conserved role for the glutathione system as the primary mediator of antioxidative electron flux.

DOI: https://doi.org/10.1038/s41467-024-55302-x