bims-mitmed 2024-12-01 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–12–01
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes.
Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models.
ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders.
Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging.
Mitochondrial dysfunction in Parkinson's disease.
Disease registries and rare disorders: The virtuous example of mitochondrial medicine.
Supplementation of Oocytes by Microinjection with Extra Copies of mtDNA Alters Metabolite Profiles and Interactions with Expressed Genes in a Tissue-Specific Manner.
Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain.
Mitochondrial Redox Status Regulates Glycogen Metabolism via Glycogen Phosphorylase Activity.
Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models.
Clinical Features, Biochemistry, Imaging, and Treatment Response in a Single-Center Cohort With Coenzyme Q10 Biosynthesis Disorders.
Mitochondria: the epigenetic regulators of ovarian aging and longevity.
The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
Beyond the cochlea: exploring the multifaceted nature of hearing loss in primary mitochondrial diseases.
PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.
Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
Ketogenic diet in adult patients with mitochondrial myopathy.

Cell Metab. 2024 Nov 23. pii: S1550-4131(24)00417-0. [Epub ahead of print]

Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.

Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N Feige, Cristina Mammucari, Umberto De Marchi.

  Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.

Keywords:  MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.10.021
Biochim Biophys Acta Mol Basis Dis. 2024 Nov 27. pii: S0925-4439(24)00561-1. [Epub ahead of print] 167567

Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes.

Milica Popovic, Lea Isermann, Simon Geißen, Katharina Senft, Theodoros Georgomanolis, Stephan Baldus, Christian Frezza, Aleksandra Trifunovic.

It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome c oxidase (CIV or COX) deficiency using a mouse model with heart and skeletal muscle-specific depletion of the COX assembly factor COX10. At three weeks of age, both tissues exhibit pronounced CIV depletion but respond differently to oxidative phosphorylation (OXPHOS) impairment. Heart-specific COX10 depletion caused severe dilated cardiomyopathy, while skeletal muscle experiences less damage. Cardiac CIV deficiency triggered extensive metabolic remodelling and stress response activation, potentially worsening cardiomyopathy, whereas skeletal muscle showed no stress response or significant metabolic changes. Our findings highlight distinct tissue capacities for managing CIV deficiency, explaining how identical primary defects can lead to different phenotypic outcomes and contribute to the heterogeneous progression of mitochondrial diseases.

DOI: https://doi.org/10.1016/j.bbadis.2024.167567
Front Neurosci. 2024 ;18 1496142

Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models.

Marcel Brügel, Ann-Sophie Kiesel, Tobias B Haack, Susana Peralta.

  Pathogenic variants in the ATAD3 gene cluster have been associated with different neurodevelopmental disorders showing clinical symptoms like global developmental delay, muscular hypotonia, cardiomyopathy, congenital cataracts, and cerebellar atrophy. ATAD3A encodes for a mitochondrial ATPase whose function is unclear and has been considered one of the five most common nuclear genes associated with mitochondrial diseases in childhood. However, the mechanism causing ATAD3-associated disorders is still unknown. In vivo models have been used to identify ATAD3 function. Here we summarize the features of mouse models with ATAD3 loss of function and Drosophila models overexpressing pathogenic ATAD3 variants. We discuss how these models have contributed to our understanding of ATAD3 function and the pathomechanism of the ATAD3-associated disease.

Keywords:  ATAD3; animal model; cholesterol; mitochondrial disease; mtDNA depletion and deletion; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2024.1496142
Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121

ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.

Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.

  The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response

DOI:  https://doi.org/10.1073/pnas.2410486121
J Inherit Metab Dis. 2024 Nov 24.

The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders.

Andrea Cortés Fernández, Jane Estrella, Devin Oglesbee, Austin A Larson, Johan L K Van Hove.

  Clinical recognition of primary mitochondrial disorders (PMD) is difficult due to the clinical and genetic heterogeneity. Whereas lactate has low sensitivity and specificity, in structured clinical studies growth differentiation factor 15 (GDF15) has shown promise with elevations in mitochondrial DNA (mtDNA)-related PMD, but its specificity has been questioned. In a tertiary care hospital-wide study, medical records were retrospectively reviewed from 418 cases where GDF15 levels were obtained by clinicians. Patients were classified into patients with PMD due to mtDNA-related defects (mtDNA maintenance, mtDNA deletions, and mtDNA-encoded tRNA variants), PMD due to structural defects or other nuclear causes, and in non-mitochondrial disease. Patients with liver disease or systemic critical illness were excluded. GDF15 was assayed in a clinical laboratory with a cutoff of 750 ng/L. There were 38 mtDNA-related PMD (GDF15 >750 pg/mL in 76%), 35 other nuclear DNA-encoded PMD or structural subunits (31% elevated GDF15), 309 non-mitochondrial disorders (13% elevated GDF15). Based on the highest Youden J-index, the optimal cut-off value to identify these target mtDNA-related disorders was 815 pg/mL, with sensitivity 76%, specificity 88%, positive predictive value of 41% and negative predictive value of 97%. At this optimized cutoff level, mtDNA-encoded PMD patients had elevated GDF15 in 76%, nuclear DNA-encoded PMD in 26%, and non-mitochondrial disorders in 11% of patients. Thus, in a real-life clinical setting, after excluding abnormal liver function and critical illness, GDF15 had good clinical utility increasing the odds at predicting mtDNA-related primary mitochondrial disorders 14-fold, but not for structural or other nuclear-encoded primary mitochondrial disorders.

Keywords:  biomarker; mitochondrial DNA deletion; mitochondrial DNA maintenance disorder; mitochondrial tRNAs

DOI:  https://doi.org/10.1002/jimd.12821
Genome Res. 2024 Nov 27. pii: gr.279072.124. [Epub ahead of print]

Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging.

Amy R Vandiver, Allen Herbst, Paul Stothard, Jonathan Wanagat.

While it is well understood that mitochondrial DNA (mtDNA) deletion mutations cause incurable diseases and contribute to aging, little is known about the transcriptional products that arise from these DNA structural variants. We hypothesized that mitochondrial genomes containing deletion mutations express chimeric mitochondrial RNAs. To test this, we analyzed human and rat RNA sequencing data to identify, quantitate, and characterize chimeric mitochondrial RNAs. We observed increased chimeric mitochondrial RNA frequency in samples from patients with mitochondrial genetic diseases and in samples from aged humans. The spectrum of chimeric mitochondrial transcripts reflected the known pattern of mtDNA deletion mutations. To test the hypothesis that mtDNA deletions induce chimeric RNA transcripts, we treated 18 mo and 34 mo rats with guanidinopropionic acid to induce high levels of skeletal muscle mtDNA deletion mutations. With mtDNA deletion induction, we demonstrate that the chimeric mitochondrial transcript frequency also increased and correlated strongly with an orthogonal DNA-based mutation assay performed on identical samples. Further, we show that the frequency of chimeric mitochondrial transcripts predicts expression of both nuclear and mitochondrial genes central to mitochondrial function, demonstrating the utility of these events as metrics of age-induced metabolic change. Mapping and quantitation of chimeric mitochondrial RNAs provides an accessible, orthogonal approach to DNA-based mutation assays, offers a potential method for identifying mitochondrial pathology in widely accessible datasets, and opens a new area of study in mitochondrial genetics and transcriptomics.

DOI: https://doi.org/10.1101/gr.279072.124
J Neural Transm (Vienna). 2024 Dec;131(12): 1415-1428

Mitochondrial dysfunction in Parkinson's disease.

Nobutaka Hattori, Shigeto Sato.

  The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.

Keywords:   PARK2 ; Autophagy-lysosome pathway; Mitochondria; Mitophagy; Parkin; Ubiquitin-proteasome pathway

DOI:  https://doi.org/10.1007/s00702-024-02863-2
Exp Neurol. 2024 Nov 25. pii: S0014-4886(24)00399-6. [Epub ahead of print] 115073

Disease registries and rare disorders: The virtuous example of mitochondrial medicine.

Daniele Orsucci, Elena Caldarazzo Ienco, Piervito Lopriore, Michelangelo Mancuso.

  Primary mitochondrial disorders (PMDs) are an extraordinarily complex group of rare disorders caused by impairment of the mitochondrial electron transport chain, or respiratory chain. Studying genotype-phenotype relationships in PMDs is a complex task. The clinical variability is large even in individuals with the same genotype, and the statistical power is low in single-center studies because of their rarity. To better define the clinical phenotypes associated with PMDs, in the last 15 years a significant multicenter effort has led to nation-wide studies on large cohorts of patients. Many national registries of mitochondrial patients have been developed in recent years, and now there is a strong effort towards international (and even global) registries. This review will revise the notable advances obtained with such studies in recent years, and will discuss the actual developments and future perspectives.

Keywords:  CPEO; Disease registries; MELAS; MERRF; Primary mitochondrial diseases; Primary mitochondrial myopathies

DOI:  https://doi.org/10.1016/j.expneurol.2024.115073
Biomolecules. 2024 Nov 20. pii: 1477. [Epub ahead of print]14(11):

Supplementation of Oocytes by Microinjection with Extra Copies of mtDNA Alters Metabolite Profiles and Interactions with Expressed Genes in a Tissue-Specific Manner.

Eryk Andreas, Alexander Penn, Takashi Okada, Justin C St John.

  Mitochondrial DNA (mtDNA) supplementation can rescue poor oocyte quality and overcome embryonic arrest. Here, we investigated a series of sexually mature pigs generated through autologous and heterologous mtDNA supplementation. Brain, liver and heart tissues underwent metabolite profiling using gas chromatography-mass spectrometry and gene expression analysis through RNA-seq. They were then assessed for mRNA-metabolite interactions. The comparison between overall mtDNA supplemented and control pigs revealed that mtDNA supplementation reduced the lipids stearic acid and elaidic acid in heart tissue. However, heterologous mtDNA supplemented-derived pigs exhibited lower levels of abundance of metabolites when compared with autologous-derived pigs. In the brain, these included mannose, mannose 6-phosphate and fructose 6-phosphate. In the liver, maltose and cellobiose, and in the heart, glycine and glutamate were affected. mRNA-metabolite pathway analysis revealed a correlation between malate and CS, ACLY, IDH2 and PKLR in the liver and glutamate and PSAT1, PHGDH, CDO1 and ANPEP in the heart. Our outcomes demonstrate that mtDNA supplementation, especially heterologous supplementation, alters the metabolite and transcriptome profiles of brain, liver, and heart tissues. This is likely due to the extensive resetting of the balance between the nuclear and mitochondrial genomes in the preimplantation embryo, which induces a series of downstream effects.

Keywords:  brain; gene expression; heart; liver; metabolic pathways; metabolite profile; mtDNA; mtDNA supplementation

DOI:  https://doi.org/10.3390/biom14111477
Free Radic Biol Med. 2024 Nov 23. pii: S0891-5849(24)01077-3. [Epub ahead of print]

Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain.

Simona Lanzillotta, Daniel Esteve, Chiara Lanzillotta, Antonella Tramutola, Ana Lloret, Elena Forte, Vito Pesce, Anna Picca, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone.

  Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies. Hence, this study investigates mitochondrial proteostasis by the mean of the mitochondrial Unfolded Protein Response (UPRmt) and the mitochondrial protein quality control (MQC) mechanisms in the context of DS, focusing on their implications in redox homeostasis in brain development. We analyzed key UPRmt markers and mitochondrial function in the frontal cortex isolated fromTs2Cje mice, a model for DS, across different developmental stages. Our results demonstrate significant alterations in UPRmt markers, particularly at postnatal day 0 (P0) and 1 month (1M). These changes indicate early UPRmt activation, primarily driven by the ATF5/GRP75 axis, although compromised by reduced levels of other components. Impaired UPRmt correlates with decreased mitochondrial activity, evidenced by reduced oxygen consumption rates and altered expression of OXPHOS complexes. Additionally, elevated oxidative stress markers such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), and protein carbonyls (PC) were observed, linking mitochondrial dysfunction to increased oxidative damage. Defects of MQC, including disrupted biogenesis, increased fission, and the activation of mitophagy were evident mostly at P0 and 1M consistent with UPRmt activation. Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje and control mice, driven by these molecular alterations. Our findings underscore the critical role of UPRmt and MQC in DS brain development, highlighting potential therapeutic targets to mitigate mitochondrial dysfunction and oxidative distress, thereby alleviating some of the neurodevelopmental and cognitive impairments associated with DS.

Keywords:  Down Syndrome; UPRmt; brain development; mitochondrial metabolism; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.043
Antioxidants (Basel). 2024 Nov 20. pii: 1421. [Epub ahead of print]13(11):

Mitochondrial Redox Status Regulates Glycogen Metabolism via Glycogen Phosphorylase Activity.

Ikko Sakamoto, Shuichi Shibuya, Hidetoshi Nojiri, Kotaro Takeno, Hiroshi Nishimune, Keisuke Yaku, Takashi Nakagawa, Muneaki Ishijima, Takahiko Shimizu.

  Mitochondria and glycogen are co-distributed in skeletal muscles to regulate the metabolic status. Mitochondria are also redox centers that regulate the muscle function during exercise. However, the pathophysiological relationship between the mitochondrial redox status and glycogen metabolism in the muscle remains unclear. In the present study, we examined the pathological effects of mitochondrial dysfunction induced by mitochondrial superoxide dismutase (SOD2) depletion on glycogen metabolism. We found that muscle glycogen was significantly accumulated in association with motor dysfunction in mice with a muscle-specific SOD2 deficiency. Muscle glycogen phosphorylase (GP-M) activity, which is a key enzyme for glycogen degradation at times when energy is needed (e.g., during exercise), was significantly decreased in the mutant muscle. Moreover, the GP-M activity on normal muscle sections decreased after treatment with paraquat, a superoxide generator. In contrast, treatment with antioxidants reversed the GP-M activity and motor disturbance of the mutant mice, indicating that GP-M activity was reversibly regulated by the redox balance. These results demonstrate that the maintenance of the mitochondrial redox balance regulates glycogen metabolism via GP-M activity.

Keywords:  SOD2; glycogen; glycogen phosphorylase; mitochondria; redox balance

DOI:  https://doi.org/10.3390/antiox13111421
Antioxidants (Basel). 2024 Nov 01. pii: 1343. [Epub ahead of print]13(11):

Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models.

Upasana Ganguly, Trae Carroll, Keith Nehrke, Gail V W Johnson.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

Keywords:  Alzheimer’s disease; Caenorhabditis elegans; aging; mitochondria; mitochondria quality control; mitophagy; model organism; neurodegeneration

DOI:  https://doi.org/10.3390/antiox13111343
Neurol Genet. 2024 Dec;10(6): e200209

Clinical Features, Biochemistry, Imaging, and Treatment Response in a Single-Center Cohort With Coenzyme Q10 Biosynthesis Disorders.

Azizia Wahedi, Sniya Sudhakar, Amanda Lam, Jose Ignacio Rodriguez Ciancio, Philippa Mills, Paul Gissen, Alice Gardham, Jogesh Kapadia, Jane Hassell, Simon Heales, Shamima Rahman.

Background and Objectives: Disorders of coenzyme Q10 (CoQ10) biosynthesis comprise a group of 11 clinically and genetically heterogeneous rare primary mitochondrial diseases. We sought to delineate clinical, biochemical, and neuroimaging features of these disorders, together with outcomes after oral CoQ10 supplementation and the utility of peripheral blood mononuclear cell (PBMNC) CoQ10 levels in monitoring therapy.
Methods: This was a retrospective cohort study, registered as an audit at a specialist pediatric hospital (Registration Number: 3318) of 14 patients with genetically confirmed CoQ10 biosynthesis deficiency, including 13 previously unreported cases.
Results: We show that oral doses of CoQ10 up to 70 mg/kg/d were needed to ameliorate neurologic features. Additional idebenone was required to control seizures in some cases, and 3 children with neonatal-onset neurologic disease died in early childhood despite receiving high-dose oral CoQ10 from birth. We also demonstrate that early diagnosis and treatment of CoQ10 deficiency with oral supplementation (30 mg/kg/d) can reverse renal manifestations and can completely prevent kidney disease over 10 years of follow-up. PBMNC CoQ10 levels increased after oral CoQ10 supplementation, demonstrating absorption of exogenous CoQ10 into the bloodstream.
Discussion: An early genome-wide diagnostic approach is needed for expeditious diagnosis of CoQ10 biosynthesis disorder because our study demonstrates that there are no pathognomonic blood, muscle, or imaging biomarkers of these diseases. Our findings indicate that earlier diagnosis and treatment with high-dose CoQ10 is key in halting progression of kidney disease or preventing it altogether. This study uses serial PBMNC CoQ10 levels to monitor therapy. Patients with genetically confirmed CoQ10 biosynthesis disorder should receive high-dose oral CoQ10 as soon as possible after presentation, regardless of genetic cause, to prevent disease progression, but parents of children with neonatal or infantile neurologic presentations should be counseled about the poor prognosis.

DOI: https://doi.org/10.1212/NXG.0000000000200209
Front Endocrinol (Lausanne). 2024 ;15 1424826

Mitochondria: the epigenetic regulators of ovarian aging and longevity.

Shalini Mani, Vidushi Srivastava, Chesta Shandilya, Aditi Kaushik, Keshav K Singh.

  Ovarian aging is a major health concern for women. Ovarian aging is associated with reduced health span and longevity. Mitochondrial dysfunction is one of the hallmarks of ovarian aging. In addition to providing oocytes with optimal energy, the mitochondria provide a co-substrate that drives epigenetic processes. Studies show epigenetic alterations, both nuclear and mitochondrial contribute to ovarian aging. Both, nuclear and mitochondrial genomes cross-talk with each other, resulting in two ways orchestrated anterograde and retrograde response that involves epigenetic changes in nuclear and mitochondrial compartments. Epigenetic alterations causing changes in metabolism impact ovarian function. Key mitochondrial co-substrate includes acetyl CoA, NAD+, ATP, and α-KG. Thus, enhancing mitochondrial function in aging ovaries may preserve ovarian function and can lead to ovarian longevity and reproductive and better health outcomes in women. This article describes the role of mitochondria-led epigenetics involved in ovarian aging and discusses strategies to restore epigenetic reprogramming in oocytes by preserving, protecting, or promoting mitochondrial function.

Keywords:  aging; epigenetics; menopause; mitochondria; ovary

DOI:  https://doi.org/10.3389/fendo.2024.1424826
Ageing Res Rev. 2024 Nov 26. pii: S1568-1637(24)00421-5. [Epub ahead of print] 102603

The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.

Xiaoding Wang, Guangyu Zhang.

  The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISRmt) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISRmt triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISRmt can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity. In this review, we provide an overview of the molecular mechanisms of the ISRmt, with a particular focus on its potential as a therapeutic target for age-related disease and the promotion of longevity.

Keywords:  FGF21; Mitochondrial integrated stress response; aging; longevity

DOI:  https://doi.org/10.1016/j.arr.2024.102603
Brain Commun. 2024 ;6(6): fcae374

Beyond the cochlea: exploring the multifaceted nature of hearing loss in primary mitochondrial diseases.

Nehzat Koohi, Sarah Holmes, Amanda Male, Doris-Eva Bamiou, Magdalena M Dudziec, Gita M Ramdharry, Chiara Pizzamiglio, Michael G Hanna, Robert D S Pitceathly, Diego Kaski.

  Primary mitochondrial diseases, with diverse systemic manifestations, often present with auditory impairments due to mitochondrial dysfunction. This study provides an in-depth exploration of auditory deficits in primary mitochondrial diseases, highlighting the impact of various pathogenic variants on both cochlea and neural/central auditory functions. An observational study involving 72 adults with primary mitochondrial diseases was conducted. Participants underwent extensive audiological evaluations including pure-tone audiometry, tympanometry, acoustic reflex thresholds, quick speech-in-noise test, listening in spatialized noise-sentences test, auditory-evoked brainstem responses and distortion product otoacoustic emissions. Multivariate analysis of covariance and logistic regression analyses assessed the influence of various pathogenic DNA variants, accounting for age, cognitive status via the Montreal Cognitive Assessment and disease severity through the Newcastle Mitochondrial Disease Adult Scale. Participants with the pathogenic m.3243A>G/T variants (m.3243A>G n = 40; m.3243A>T n = 1) exhibited significant elevations in pure-tone audiometry thresholds, especially at high frequencies, suggesting cochlea involvement. Notably, the listening in spatialized noise-sentences test showed significant spatial processing deficits in the m.3243A>G/T group, possibly indicating a unique mutation-specific impact on central auditory processing. Auditory-evoked brainstem response results highlighted a higher likelihood of auditory brainstem response abnormalities in this group, further substantiating neural/central auditory pathway involvement. This study emphasizes the heterogeneous nature of hearing impairment in primary mitochondrial diseases, with a genotype-phenotype correlation, particularly in the m.3243A>G/T group. These insights advocate for personalized, genotype-specific auditory assessments and targeted management strategies. Conventional hearing aids and cochlear implants are ineffective for those with central auditory dysfunctions related to mitochondrial mutations. There is an urgent need for innovative rehabilitation strategies catering for both cochlear and neural/central auditory pathways.

Keywords:  auditory brainstem responses; auditory processing; hearing loss; mitochondrial disease; spatial processing disorder

DOI:  https://doi.org/10.1093/braincomms/fcae374
Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2416882121

PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.

Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A Dibernardo, Favour N Esedebe, Vipul Bhatia, Mingqi Han, Evan R Abt, Jung Wook Park, Sanaz Memarzadeh, David B Shackelford, John K Lee, Thomas G Graeber, Orian S Shirihai, Owen N Witte.

  Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.

Keywords:  ASCL1; PGC-1a; lung cancer; oxidative phosphorylation; prostate cancer

DOI:  https://doi.org/10.1073/pnas.2416882121
Mol Brain. 2024 Nov 27. 17(1): 87

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Ozan Baytas, Shawn M Davidson, Julie A Kauer, Eric M Morrow.

  Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2-null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2-null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2-null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.

Keywords:  Cognitive development; Disease; GPT2; Glutamate; Intellectual disability; Neurometabolic; Neurometabolism; Synapse; TCA cycle

DOI:  https://doi.org/10.1186/s13041-024-01154-x
Mol Genet Metab. 2024 Nov 10. pii: S1096-7192(24)00494-3. [Epub ahead of print]143(4): 108610

Ketogenic diet in adult patients with mitochondrial myopathy.

Heidi E E Zweers, Sophie H Kroesen, Gijsje Beerlink, Elke Buit, Karlijn Gerrits, Astrid Dorhout, Annemiek M J van Wegberg, Mirian C H Janssen, Saskia B Wortmann, Silvie Timmers, Christiaan G J Saris.

   BACKGROUND: This study aimed to explore the feasibility, safety and efficacy of a Modified Atkins Diet (MAD) in patients with mitochondrial myopathy (MM).
METHODS: Patients with genetically proven mitochondrial disorder and exercise intolerance or muscle weakness followed a twelve week MAD. Feasibility was measured by diet duration and ketone levels. Safety was assessed by monitoring adverse events (AE). Efficacy was assessed by a maximal incremental test and a muscle performance test.
RESULTS: Eight out of twenty patients completed the twelve week intervention. Reasons to discontinue were the occurrence of AE: rhabdomyolysis (n = 3), vomiting (n = 1), fatigue (n = 6), constipation (n = 1), in combination with a lack of improvement and adherence difficulties. On an individual level, various positive effects were reported including improvements in VO2peak (n = 6), anaerobic threshold (n = 9), muscle fatigue resistance (n = 5), muscle strength (n = 7), fatigue (n = 6), glucose tolerance (n = 7), migraine (n = 3), sleep (n = 3), and gastrointestinal complaints (n = 2). Lipid profile improved and thirteen patients lost weight. All patients with mitochondrial DNA (mtDNA) deletions, experienced muscle related AE. The five patients with the m.3243A>G mutation achieved the longest diet duration.
DISCUSSION/CONCLUSION: MAD feasibility, safety and efficacy is variable in MD patients. MAD appears to be unsuitable for MD patients with mtDNA deletions. All patients should be monitored closely for adverse events when initiating the diet. Further research should focus on predictive factors to consider the diet, effectiveness of less stringent carbohydrate restricted diets.

Keywords:  Adverse event; Ketogenic diet; Maximal incremental testing; Mitochondrial DNA deletion; Mitochondrial myopathy; Modified Atkins diet

DOI:  https://doi.org/10.1016/j.ymgme.2024.108610