bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–12–24
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial quality control pathways sense mitochondrial protein import.
  2. Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
  3. Muscle immune cells protect mitochondrial organelles during exercise.
  4. FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
  5. MELAS-Derived Neurons Functionally Improve by Mitochondrial Transfer from Highly Purified Mesenchymal Stem Cells (REC).
  6. Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals.
  7. Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
  8. PNPLA3-associated mitochondrial dysfunction.
  9. Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
  10. Mitochondrial quality control via organelle and protein degradation.
  11. Leber hereditary optic neuropathy gene therapy.
  12. Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
  13. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
  14. The adverse effects of vitrification on mouse embryo development and metabolic phenotype in offspring.
  15. From Mother to Infant, from Placenta to Gut: Understanding Varied Microbiome Profiles in Neonates.
  16. Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study.
  17. Mitochondrial Oxidative Phosphorylation in Viral Infections.
  18. Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.
  19. Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex.
  1. Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]
    Mitochondrial quality control pathways sense mitochondrial protein import.
    Laurie P Lee-Glover, Timothy E Shutt.
      Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.
    Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.1016/j.tem.2023.11.004
  2. Biomolecules. 2023 Dec 13. pii: 1789. [Epub ahead of print]13(12):
    Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
    Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Jose Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Mónica Álvarez-Córdoba, Manuel Munuera-Cabeza, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Antonio Sánchez-Alcázar.
      Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
    Keywords:  ageing; mitochondria; mitochondrial biogenesis; mitochondrial diseases; mitochondrial dynamics; mitochondrial quality control mechanisms; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases; therapeutic target
    DOI:  https://doi.org/10.3390/biom13121789
  3. Nature. 2024 Jan;625(7993): 35-36
    Muscle immune cells protect mitochondrial organelles during exercise.
    Gerald Coulis, S Armando Villalta.
      
    Keywords:  Cell biology; Immunology; Physiology
    DOI:  https://doi.org/10.1038/d41586-023-03972-w
  4. Trends Mol Med. 2023 Dec 19. pii: S1471-4914(23)00279-4. [Epub ahead of print]
    FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
    Kun Gao, Xiayun Xu, Chenji Wang.
      Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.
    Keywords:  BNIP3/BNIP3L; FBXL4; MTDPS13; mitochondria; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1016/j.molmed.2023.11.017
  5. Int J Mol Sci. 2023 Dec 06. pii: 17186. [Epub ahead of print]24(24):
    MELAS-Derived Neurons Functionally Improve by Mitochondrial Transfer from Highly Purified Mesenchymal Stem Cells (REC).
    Lu Liu, Jiahao Yang, Yoshinori Otani, Takahiro Shiga, Akihiro Yamaguchi, Yasuaki Oda, Miho Hattori, Tsukimi Goto, Shuichi Ishibashi, Yuki Kawashima-Sonoyama, Takaya Ishihara, Yumi Matsuzaki, Wado Akamatsu, Masashi Fujitani, Takeshi Taketani.
      Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.
    Keywords:  MELAS; mesenchymal stem cells (MSCs); mitochondrial transfer; rapidly expanding clones (RECs)
    DOI:  https://doi.org/10.3390/ijms242417186
  6. Front Neurol. 2023 ;14 1292320
    Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals.
    Toby Charles Major, Eszter Sara Arany, Katherine Schon, Magdolna Simo, Veronika Karcagi, Jelle van den Ameele, Patrick Yu Wai Man, Patrick F Chinnery, Catarina Olimpio, Rita Horvath.
       Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterized by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA); however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30.
    Case Presentations: In this study, we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several-year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals.
    Conclusion: This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analog idebenone.
    Keywords:  DNA-J heat shock protein family (Hsp40) member C30 (DNAJC30); Leber hereditary optic neuropathy (LHON); autosomal recessive LHON (arLHON); c.152A>G (p.Tyr51Cys); idebenone; mitochondrial LHON (mtLHON); recessive optic neuropathy
    DOI:  https://doi.org/10.3389/fneur.2023.1292320
  7. Nat Commun. 2023 Dec 20. 14(1): 8474
    Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
    Cecilia Patitucci, Juan Diego Hernández-Camacho, Elodie Vimont, Sonny Yde, Thomas Cokelaer, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Anastasia Gazi, Ivan Nemazanyy, David A Stroud, Daniella H Hock, Erminia Donnarumma, Timothy Wai.
      Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.
    DOI:  https://doi.org/10.1038/s41467-023-44143-9
  8. Nat Genet. 2023 Dec 18.
    PNPLA3-associated mitochondrial dysfunction.
    Kyle Vogan.
      
    DOI:  https://doi.org/10.1038/s41588-023-01636-z
  9. Nature. 2023 Dec 20.
    Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
    Chrysanthi Moschandrea, Vangelis Kondylis, Ioannis Evangelakos, Marija Herholz, Farina Schneider, Christina Schmidt, Ming Yang, Sandra Ehret, Markus Heine, Michelle Y Jaeckstein, Karolina Szczepanowska, Robin Schwarzer, Linda Baumann, Theresa Bock, Efterpi Nikitopoulou, Susanne Brodesser, Marcus Krüger, Christian Frezza, Joerg Heeren, Aleksandra Trifunovic, Manolis Pasparakis.
      Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes, which shows that the accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed an impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in intestinal epithelial cells. DARS2 deficiency caused a distinct lack of mature chylomicrons concomitant with a progressive dispersal of the Golgi apparatus in proximal enterocytes. This finding suggests that mitochondrial dysfunction results in impaired trafficking of chylomicrons from the endoplasmic reticulum to the Golgi, which in turn leads to storage of dietary lipids in large cytoplasmic LDs. Taken together, these results reveal a role for mitochondria in dietary lipid transport in enterocytes, which might be relevant for understanding the intestinal defects observed in patients with mitochondrial disorders5.
    DOI:  https://doi.org/10.1038/s41586-023-06857-0
  10. J Biochem. 2023 Dec 15. pii: mvad106. [Epub ahead of print]
    Mitochondrial quality control via organelle and protein degradation.
    Koji Yamano, Hiroki Kinefuchi, Waka Kojima.
      Mitochondria are essential eukaryotic organelles that produce ATP as well as synthesize various macromolecules. They also participate in signaling pathways such as the innate immune response and apoptosis. These diverse functions are performed by >1000 different mitochondrial proteins. Although mitochondria are continuously exposed to potentially damaging conditions such as reactive oxygen species, proteases/peptidases localized in different mitochondrial sub-compartments, termed mitoproteases, maintain mitochondrial quality and integrity. In addition to processing incoming precursors and degrading damaged proteins, mitoproteases also regulate metabolic reactions, mitochondrial protein half-lives, and gene transcription. Impaired mitoprotease function is associated with various pathologies. In this review, we highlight recent advances in our understanding of mitochondrial quality control regulated by autophagy, ubiquitin-proteasomes, and mitoproteases.
    Keywords:  autophagy; mitophagy; peptidase; protease; ubiquitin
    DOI:  https://doi.org/10.1093/jb/mvad106
  11. Curr Opin Ophthalmol. 2023 Dec 21.
    Leber hereditary optic neuropathy gene therapy.
    Byron L Lam.
       PURPOSE OF REVIEW: To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON).
    RECENT FINDINGS: Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes. Final mean BCVA levels after gene therapy were in the range of ∼1.3 logMAR (20/400) bilaterally.
    SUMMARY: Bilateral partial improvement with unilateral LHON gene therapy was unanticipated and may be due to treatment efficacy, natural history, learning effect, and other mediators. The overall efficacy is limited given the final BCVA levels. The sequential progressive visual loss and varied occurrence of spontaneous partial improvement in LHON confound trial results. Future clinical trials with randomization of patients to a group not receiving gene therapy in either eye would help to assess treatment effect. Promising future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of the wild-type mitochondrial DNA into the mitochondria and CRISPR-free, RNA-free mitochondrial base editing systems. Signs of anatomical optic nerve damage and objective retinal ganglion cell dysfunction are evident in the asymptomatic eyes of LHON patients experiencing unilateral visual loss, indicating the therapeutic window is narrowing before onset of visual symptoms. Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy holds the promise of a more advantageous approach to achieve optimal visual outcome by reducing disease penetrance and mitigating retinal ganglion cell loss when optic neuropathy develops.
    DOI:  https://doi.org/10.1097/ICU.0000000000001028
  12. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]
    Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
    Riley J Wedan, Jacob Z Longenecker, Sara M Nowinski.
      Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.
    Keywords:  fatty acids; inborn errors of metabolism; lipid metabolism; lipids; mitochondria; mitochondrial fatty acid synthesis; mouse models; mtFAS
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.017
  13. Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):
    Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
    Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.
      Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.
    Keywords:  ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response
    DOI:  https://doi.org/10.3390/ijms242417423
  14. FASEB J. 2024 Jan;38(1): e23372
    The adverse effects of vitrification on mouse embryo development and metabolic phenotype in offspring.
    Qiaoyu Chen, Dan Zhou, Changxin Wang, Mingming Ye, Yanping Jia, Binya Liu, Orhan Bukulmez, Robert J Norman, Hanxin Hu, Shu-Biu Yeung, Xiaoming Teng, Wenqiang Liu, Miaoxin Chen.
      Embryo vitrification is a standard procedure in assisted reproductive technology. Previous studies have shown that frozen embryo transfer is associated with an elevated risk of adverse maternal and neonatal outcomes. This study aimed to explore the effects of mouse blastocyst vitrification on the phenotype of vitrified-warmed blastocysts, their intrauterine and postnatal development, and the long-term metabolic health of the derived offspring. The vitrified-warmed blastocysts (IVF + VT group) exhibited reduced mitochondrial activity, increased apoptotic levels, and decreased cell numbers when compared to the fresh blastocysts (IVF group). Implantation rates, live pup rates, and crown-rump length at E18.5 were not different between the two groups. However, there was a significant decrease in fetal weight and fetal/placental weight ratio in the IVF + VT group. Furthermore, the offspring of the IVF + VT group at an age of 36 weeks had reduced whole energy consumption, impaired glucose and lipid metabolism when compared with the IVF group. Notably, RNA-seq results unveiled disturbed hepatic gene expression in the offspring from vitrified-warmed blastocysts. This study revealed the short-term negative impacts of vitrification on embryo and fetal development and the long-term influence on glucose and lipid metabolism that persist from the prenatal stage into adulthood in mice.
    Keywords:  blastocyst; cryopreservation; embryo vitrification; frozen embryo transfer; reactive oxygen stress
    DOI:  https://doi.org/10.1096/fj.202301774RR
  15. Metabolites. 2023 Dec 05. pii: 1184. [Epub ahead of print]13(12):
    From Mother to Infant, from Placenta to Gut: Understanding Varied Microbiome Profiles in Neonates.
    Riadh Cheddadi, Venkata Yeramilli, Colin Martin.
      The field of human microbiome and gut microbial diversity research has witnessed a profound transformation, driven by advances in omics technologies. These advancements have unveiled essential connections between microbiome alterations and severe conditions, prompting the development of new frameworks through epidemiological studies. Traditionally, it was believed that each individual harbored unique microbial communities acquired early in life, evolving over the course of their lifetime, with little acknowledgment of any prenatal microbial development, but recent research challenges this belief. The neonatal microbiome's onset, influenced by factors like delivery mode and maternal health, remains a subject of intense debate, hinting at potential intrauterine microbial processes. In-depth research reveals associations between microbiome profiles and specific health outcomes, ranging from obesity to neurodevelopmental disorders. Understanding these diverse microbiome profiles is essential for unraveling the intricate relationships between the microbiome and health outcomes.
    Keywords:  animal models; maternal influence; maternal microbiome; metabolites; microbiome transfer; neonatal microbiome; omics; pregnancy
    DOI:  https://doi.org/10.3390/metabo13121184
  16. Mov Disord. 2023 Dec 23.
    Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study.
    European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)
       BACKGROUND: Friedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death.
    OBJECTIVES: To investigate predictors of survival in FA.
    METHODS: Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509) we enrolled genetically confirmed FA patients at 11 tertiary centers and followed them in yearly intervals. We investigated overall survival applying the Kaplan-Meier method, life tables, and log-rank test. We explored prognostic factors applying Cox proportional hazards regression and subsequently built a risk score which was assessed for discrimination and calibration performance.
    RESULTS: Between September 2010 and March 2017, we enrolled 631 FA patients. Median age at inclusion was 31 (range, 6-76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10-year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08-2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34-6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05-5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10-year survival (log-rank test P < 0.001).
    CONCLUSIONS: Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  Friedreich's ataxia; cardiomyopathy; diabetes mellitus; disability stage; survival
    DOI:  https://doi.org/10.1002/mds.29687
  17. Viruses. 2023 Dec 04. pii: 2380. [Epub ahead of print]15(12):
    Mitochondrial Oxidative Phosphorylation in Viral Infections.
    Neeraja Purandare, Esha Ghosalkar, Lawrence I Grossman, Siddhesh Aras.
      Mitochondria have been identified as the "powerhouse" of the cell, generating the cellular energy, ATP, for almost seven decades. Research over time has uncovered a multifaceted role of the mitochondrion in processes such as cellular stress signaling, generating precursor molecules, immune response, and apoptosis to name a few. Dysfunctional mitochondria resulting from a departure in homeostasis results in cellular degeneration. Viruses hijack host cell machinery to facilitate their own replication in the absence of a bonafide replication machinery. Replication being an energy intensive process necessitates regulation of the host cell oxidative phosphorylation occurring at the electron transport chain in the mitochondria to generate energy. Mitochondria, therefore, can be an attractive therapeutic target by limiting energy for viral replication. In this review we focus on the physiology of oxidative phosphorylation and on the limited studies highlighting the regulatory effects viruses induce on the electron transport chain.
    Keywords:  ATP synthase; NADH dehydrogenase; cytochrome bc1 complex; cytochrome c oxidase; oxidative phosphorylation; reactive oxygen species; succinate dehydrogensase
    DOI:  https://doi.org/10.3390/v15122380
  18. Nat Aging. 2023 Dec 15.
    Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.
    Andrea Cipriano, Mahdi Moqri, Sun Y Maybury-Lewis, Ryan Rogers-Hammond, Tineke Anna de Jong, Alexander Parker, Sajede Rasouli, Hans Robert Schöler, David A Sinclair, Vittorio Sebastiano.
      Over the past decade, there has been a dramatic increase in efforts to ameliorate aging and the diseases it causes, with transient expression of nuclear reprogramming factors recently emerging as an intriguing approach. Expression of these factors, either systemically or in a tissue-specific manner, has been shown to combat age-related deterioration in mouse and human model systems at the cellular, tissue and organismal level. Here we discuss the current state of epigenetic rejuvenation strategies via partial reprogramming in both mouse and human models. For each classical reprogramming factor, we provide a brief description of its contribution to reprogramming and discuss additional factors or chemical strategies. We discuss what is known regarding chromatin remodeling and the molecular dynamics underlying rejuvenation, and, finally, we consider strategies to improve the practical uses of epigenetic reprogramming to treat aging and age-related diseases, focusing on the open questions and remaining challenges in this emerging field.
    DOI:  https://doi.org/10.1038/s43587-023-00539-2
  19. Nat Commun. 2023 Dec 16. 14(1): 8380
    Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex.
    Alexander Popov, Nadezda Brazhe, Kseniia Morozova, Konstantin Yashin, Maxim Bychkov, Olga Nosova, Oksana Sutyagina, Alexey Brazhe, Evgenia Parshina, Li Li, Igor Medyanik, Dmitry E Korzhevskii, Zakhar Shenkarev, Ekaterina Lyukmanova, Alexei Verkhratsky, Alexey Semyanov.
      How aging affects cells of the human brain active milieu remains largely unknown. Here, we analyze astrocytes and neurons in the neocortical tissue of younger (22-50 years) and older (51-72 years) adults. Aging decreases the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The protein-to-lipid ratio decreases in astrocytes and increases in neurons. Aged astrocytes show morphological atrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Atrophy correlates with the loss of gap junction coupling between astrocytes and increased input resistance. Aging is accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling is observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of cortical astrocytes, but not neurons.
    DOI:  https://doi.org/10.1038/s41467-023-44192-0
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