bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–12–10
eightteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Laboratory and Genotype Relationship of Patients with SDHA-Related Mitochondrial Disease.
  2. Endocrine features of primary mitochondrial diseases.
  3. The contribution of mitochondria to age-related skeletal muscle wasting: A sex-specific perspective.
  4. Skeletal muscle mitochondria demonstrate similar respiration per cristae surface area independent of training status and sex in healthy humans.
  5. Long-Term Safety of Systemic Ozone Therapy in a Patient With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS).
  6. CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.
  7. Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging.
  8. Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.
  9. Amyotrophic Lateral Sclerosis with SOD1 Mutation Presenting with Progressive Cerebellar Ataxia.
  10. Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
  11. A monolysocardiolipin-cytochrome c peroxidase causes defects in Barth syndrome.
  12. Mitochondrial recruitment in myelin: an anchor for myelin dynamics and plasticity?
  13. Multimodal assessment of mitochondrial function in Parkinson's disease.
  14. Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome.
  15. Dynamics of mitochondrial membranes under photo-oxidative stress with high spatiotemporal resolution.
  16. Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
  17. The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
  18. Replenishing NAD+ content reduces aspects of striated muscle disease in a dog model of Duchenne muscular dystrophy.
  1. Mol Syndromol. 2023 Dec;14(6): 459-460
    Laboratory and Genotype Relationship of Patients with SDHA-Related Mitochondrial Disease.
    Burcu Civelek Ürey, Ahmet Cevdet Ceylan, Büşranur Çavdarlı, Ayşegül Neşe Çıtak Kurt, Oya Kıreker Köylü, Burak Yürek, Çiğdem Seher Kasapkara.
      
    Keywords:  Leigh syndrome phenotype; Metabolic diseases; Mitochondrial disease; Succinate dehydrogenase deficiency; Whole-exome sequencing
    DOI:  https://doi.org/10.1159/000531668
  2. Curr Opin Endocrinol Diabetes Obes. 2023 Dec 05.
    Endocrine features of primary mitochondrial diseases.
    Lindsay Romo, Nina B Gold, Melissa A Walker.
       PURPOSE OF REVIEW: Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have clinical features that are distinct from the more common forms. We provide an overview of mitochondrial disorder genetics and phenotypes, focusing on recent studies regarding identification and treatment of associated endocrinopathies.
    RECENT FINDINGS: Known endocrine phenotypes of mitochondrial disorders continue to expand, and now include growth hormone deficiency, hypogonadism, precocious puberty, hypoparathyroidism, hypo- and hyperthyroidism, diabetes, and adrenal insufficiency. Recent studies suggest several genotype-phenotype correlations, including those related to nuclear variants. Diagnosis is important, as special considerations should be made in the management of endocrinopathies in mitochondrial patients. Finally, new mitochondrial replacement strategies may soon be available for women interested in preventing mitochondrial disease transmission to offspring.
    SUMMARY: Patients with multiple endocrinopathies or atypical endocrinopathies should be evaluated for primary mitochondrial disease, as a diagnosis may impact management of these individuals.
    DOI:  https://doi.org/10.1097/MED.0000000000000848
  3. Life Sci. 2023 Nov 30. pii: S0024-3205(23)00959-1. [Epub ahead of print]336 122324
    The contribution of mitochondria to age-related skeletal muscle wasting: A sex-specific perspective.
    Alessandro Nuccio, Rita Nogueira-Ferreira, Alexandra Moreira-Pais, Alessandro Attanzio, José Alberto Duarte, Claudio Luparello, Rita Ferreira.
      As people age, their skeletal muscle (SkM) experiences a decline in mitochondrial functionality and density, which leads to decreased energy production and increased generation of reactive oxygen species. This cascade of events, in turn, might determine the loss of SkM mass, strength and quality. Even though the mitochondrial processes dysregulated by aging, such as oxidative phosphorylation, mitophagy, antioxidant defenses and mtDNA transcription, are the same in both sexes, mitochondria age differently in the SkM of men and women. Indeed, the onset and magnitude of the impairment of these processes seem to be influenced by sex-specific factors. Sexual hormones play a pivotal role in the regulation of SkM mass through both genomic and non-genomic mechanisms. However, the precise mechanisms by which these hormones regulate mitochondrial plasticity in SkM are not fully understood. Although the presence of estrogen receptors in mitochondria is recognized, it remains unclear whether androgen receptors affect mitochondrial function. This comprehensive review critically dissects the current knowledge on the interplay of sex in the aging of SkM, focusing on the role of sex hormones and the corresponding signaling pathways in shaping mitochondrial plasticity. Improved knowledge on the sex dimorphism of mitochondrial aging may lead to sex-tailored interventions that target mitochondrial health, which could be effective in slowing or preventing age-related muscle loss.
    Keywords:  Androgens; Estrogens; Mitochondria remodeling; Sarcopenia; Sexual dimorphism
    DOI:  https://doi.org/10.1016/j.lfs.2023.122324
  4. J Physiol. 2023 Dec 05.
    Skeletal muscle mitochondria demonstrate similar respiration per cristae surface area independent of training status and sex in healthy humans.
    Camilla Tvede Schytz, Niels Ørtenblad, Anne-Kristine Meinild Lundby, Robert Acton Jacobs, Joachim Nielsen, Carsten Lundby.
      The impact of training status and sex on intrinsic skeletal muscle mitochondrial respiratory capacity remains unclear. We examined this by analysing human skeletal muscle mitochondrial respiration relative to mitochondrial volume and cristae density across training statuses and sexes. Mitochondrial cristae density was estimated in skeletal muscle biopsies originating from previous independent studies. Participants included females (n = 12) and males (n = 41) across training statuses ranging from untrained (UT, n = 8), recreationally active (RA, n = 9), active-to-elite runners (RUN, n = 27) and cross-country skiers (XC, n = 9). The XC and RUN groups demonstrated higher mitochondrial volume density than the RA and UT groups while all active groups (RA, RUN and XC) displayed higher mass-specific capacity of oxidative phosphorylation (OXPHOS) and mitochondrial cristae density than UT. Differences in OXPHOS diminished between active groups and UT when normalising to mitochondrial volume density and were lost when normalising to muscle cristae surface area density. Moreover, active females (n = 6-9) and males (n = 15-18) did not differ in mitochondrial volume and cristae density, OXPHOS, or when normalising OXPHOS to mitochondrial volume density and muscle cristae surface area density. These findings demonstrate: (1) differences in OXPHOS between active and untrained individuals may be explained by both higher mitochondrial volume and cristae density in active individuals, with no difference in intrinsic mitochondrial respiratory capacity (OXPHOS per muscle cristae surface area density); and (2) no sex differences in mitochondrial volume and cristae density or mass-specific and normalised OXPHOS. This highlights the importance of normalising OXPHOS to muscle cristae surface area density when studying skeletal muscle mitochondrial biology. KEY POINTS: Oxidative phosphorylation is the mitochondrial process by which ATP is produced, governed by the electrochemical gradient across the inner mitochondrial membrane with infoldings named cristae. In human skeletal muscle, the mass-specific capacity of oxidative phosphorylation (OXPHOS) can change independently of shifts in mitochondrial volume density, which may be attributed to variations in cristae density. We demonstrate that differences in skeletal muscle OXPHOS between healthy females and males, ranging from untrained to elite endurance athletes, are matched by differences in cristae density. This suggests that higher OXPHOS in skeletal muscles of active individuals is attributable to an increase in the density of cristae. These findings broaden our understanding of the variability in human skeletal muscle OXPHOS and highlight the significance of cristae, specific to mitochondrial respiration.
    Keywords:  intrinsic mitochondrial respiratory capacity; mitochondria; mitochondrial cristae density; oxidative phosphorylation; sex; skeletal muscle; training status
    DOI:  https://doi.org/10.1113/JP285091
  5. Cureus. 2023 Nov;15(11): e48261
    Long-Term Safety of Systemic Ozone Therapy in a Patient With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS).
    Daniele Romanello, Sara Rotunno, Mauro Martinelli.
      A patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a rare mitochondrial disease characterized by myopathy, epilepsy, encephalopathy, acidosis, and recurrent cerebral ischemic episodes, underwent systemic hematogenous ozone therapy for 17 years. Despite advancements in the study of mitochondrial diseases, there are currently no available treatments for MELAS. The patient in this case has received over 280 sessions of systemic hematic ozone therapy since 2003 (from the age of 10 years) till the time of publication, without reporting any adverse effects, achieving a normal level of development considering the comorbidities. Possible mechanisms of action of systemic hematogenous ozone therapy include improved efficiency of the mitochondrial oxidative chain through the induction of antioxidant enzymes (catalase, superoxide dismutases {SOD}, peroxidase). More studies are needed to evaluate the actual safety of long-term systemic hematogenous ozone therapy in patients with mitochondrial diseases.
    Keywords:  melas syndrome; mitochondrial disease; oxidative stress; ozone therapy; safety study
    DOI:  https://doi.org/10.7759/cureus.48261
  6. ACS Chem Biol. 2023 Dec 06.
    CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.
    Tanja Sack, Piriththiv Dhavarasa, Daniel Szames, Siobhan O'Brien, Stephane Angers, Shana O Kelley.
      A major impediment to the characterization of mtDNA repair mechanisms in comparison to nuclear DNA repair mechanisms is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of an mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response. Using mitochondria-targeted doxorubicin (mtDox), we generate mtDNA double-strand breaks (mtDSBs) specifically in this organelle. Combined with an untargeted doxorubicin (Dox) screen, we identify genes with significantly greater essentiality during mitochondrial versus nuclear DNA damage. We characterize the essentiality of our top hit, WRNIP1─observed here for the first time to respond to mtDNA damage. We further investigate the mitochondrial role of WRNIP1 in innate immune signaling and nuclear genome maintenance, outlining a model that experimentally supports mitochondrial turnover in response to mtDSBs.
    DOI:  https://doi.org/10.1021/acschembio.3c00620
  7. Front Physiol. 2023 ;14 1284410
    Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging.
    Ines Martic, Federica Papaccio, Barbara Bellei, Maria Cavinato.
      Aging of human skin is a complex process leading to a decline in homeostasis and regenerative potential of this tissue. Mitochondria are important cell organelles that have a crucial role in several cellular mechanisms such as energy production and free radical maintenance. However, mitochondrial metabolism as well as processes of mitochondrial dynamics, biogenesis, and degradation varies considerably among the different types of cells that populate the skin. Disturbed mitochondrial function is known to promote aging and inflammation of the skin, leading to impairment of physiological skin function and the onset of skin pathologies. In this review, we discuss the essential role of mitochondria in different skin cell types and how impairment of mitochondrial morphology, physiology, and metabolism in each of these cellular compartments of the skin contributes to the process of skin aging.
    Keywords:  aging; mitochondria; skin; skin cells; skin homeostasis
    DOI:  https://doi.org/10.3389/fphys.2023.1284410
  8. EXCLI J. 2023 ;22 1077-1091
    Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.
    Prakash Chermakani, Poigaialwar Gowri, Shanmugam Mahesh Kumar, Periasamy Sundaresan.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thirty probands displaying symptoms consistent with LHON have undergone whole mitochondrial and whole exome sequencing. Interestingly, whole mtDNA sequencing revealed primary mtDNA mutations in 30 % of the probands (n=9), secondary mtDNA mutations in 40 % of the probands (n=12) and no mitochondrial changes in 30 % of individuals (n=9). Further, WES analysis determined pathogenic mutations in 11 different nuclear genes, especially in cases with secondary mtDNA mutations (n=6) or no mtDNA mutations (n=6). These findings provide valuable insight into LHON genetic predisposition, particularly in cases lacking primary mtDNA mutations. See also Figure 1(Fig. 1).
    Keywords:  arLHON; mito-nuclear genetic factors; mitochondrial complex I disorder; optic atrophy and vision loss; retinoganglion degeneration
    DOI:  https://doi.org/10.17179/excli2023-6297
  9. Cerebellum. 2023 Dec 05.
    Amyotrophic Lateral Sclerosis with SOD1 Mutation Presenting with Progressive Cerebellar Ataxia.
    Marta Sequeira, Filipe Godinho, João Lourenço.
      Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder that affects upper and lower motor neurons. SOD1 mutations are the second most commonly found in familial and sporadic cases. We describe a patient with a homozygous pathogenic mutation in SOD1 gene that presented with a progressive cerebellar ataxia and ultimately developed a complex phenotype of cerebellar ataxia and motor neuron disease. The linkage between the cerebellum and ALS is shortly discussed.
    Keywords:  Amyotrophic lateral sclerosis; Cerebellar ataxia; Cerebellum; SOD1
    DOI:  https://doi.org/10.1007/s12311-023-01643-0
  10. J Obes Metab Syndr. 2023 Dec 05.
    Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
    Soyeon Shin, Jaeyoung Kim, Ju Yeon Lee, Jun Kim, Chang-Myung Oh.
      Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is characterized by hepatic steatosis and metabolic dysfunction and is often associated with obesity and insulin resistance. Recent research indicates a rapid escalation in MASLD cases, with projections suggesting a doubling in the United States by 2030. This review focuses on the central role of mitochondria in the pathogenesis of MASLD and explores potential therapeutic interventions. Mitochondria are dynamic organelles that orchestrate hepatic energy production and metabolism and are critically involved in MASLD. Dysfunctional mitochondria contribute to lipid accumulation, inflammation, and liver fibrosis. Genetic associations further underscore the relationship between mitochondrial dynamics and MASLD susceptibility. Although U.S. Food and Drug Administration-approved treatments for MASLD remain elusive, ongoing clinical trials have highlighted promising strategies that target mitochondrial dysfunction, including vitamin E, metformin, and glucagon-like peptide-1 receptor agonists. In preclinical studies, novel therapeutics, including nicotinamide adenine dinucleotide+ precursors, urolithin A, spermidine, and mitoquinone, have shown beneficial effects, such as improving mitochondrial quality control, reducing oxidative stress, and ameliorating hepatic steatosis and inflammation. In conclusion, mitochondrial dysfunction is central to MASLD pathogenesis. The innovative mitochondria-targeted approaches discussed in this review offer a promising avenue for reducing the burden of MASLD and improving global quality of life.
    Keywords:  Metabolic dysfunction-associated steatotic liver disease; Mitochondria; Mitochondrial quality control
    DOI:  https://doi.org/10.7570/jomes23054
  11. Nat Metab. 2023 Dec 04.
    A monolysocardiolipin-cytochrome c peroxidase causes defects in Barth syndrome.
      
    DOI:  https://doi.org/10.1038/s42255-023-00925-5
  12. Neural Regen Res. 2024 Jul 01. 19(7): 1401-1402
    Mitochondrial recruitment in myelin: an anchor for myelin dynamics and plasticity?
    Jean-David M Gothié, Timothy E Kennedy.
      
    DOI:  https://doi.org/10.4103/1673-5374.387982
  13. Brain. 2023 Dec 07. pii: awad364. [Epub ahead of print]
    Multimodal assessment of mitochondrial function in Parkinson's disease.
    Thomas Payne, Toby Burgess, Stephen Bradley, Sarah Roscoe, Matilde Sassani, Mark J Dunning, Dena Hernandez, Sonja Scholz, Alisdair McNeill, Rosie Taylor, Li Su, Iain Wilkinson, Thomas Jenkins, Heather Mortiboys, Oliver Bandmann.
      The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects. Sixty participants (35 patients with Parkinson's disease and 25 healthy controls) underwent 31P-MRS for quantification of energy-rich metabolites [ATP, inorganic phosphate (Pi) and phosphocreatine] in putamen and midbrain. In parallel, skin biopsies were obtained from all research participants to establish fibroblast cell lines for subsequent quantification of total intracellular ATP and mitochondrial membrane potential (MMP) as well as mitochondrial and lysosomal morphology, using high content live cell imaging. Lower MMP correlated with higher intracellular ATP (r = -0.55, P = 0.0016), higher mitochondrial counts (r  = -0.72, P  < 0.0001) and higher lysosomal counts (r = -0.62, P  = 0.0002) in Parkinson's disease patient-derived fibroblasts only, consistent with impaired mitophagy and mitochondrial uncoupling. 31P-MRS-derived posterior putaminal Pi/ATP ratio variance was considerably greater in Parkinson's disease than in healthy controls (F-tests, P  = 0.0036). Furthermore, elevated 31P-MRS-derived putaminal, but not midbrain Pi/ATP ratios (indicative of impaired oxidative phosphorylation) correlated with both greater mitochondrial (r  = 0.37, P  = 0.0319) and lysosomal counts (r  = 0.48, P  = 0.0044) as well as lower MMP in both short (r  = -0.52, P  = 0.0016) and long (r  = -0.47, P  = 0.0052) mitochondria in Parkinson's disease. Higher 31P-MRS midbrain phosphocreatine correlated with greater risk of rapid disease progression (r  = 0.47, P  = 0.0384). Our data suggest that impaired oxidative phosphorylation in the striatal dopaminergic nerve terminals exceeds mitochondrial dysfunction in the midbrain of patients with early Parkinson's disease. Our data further support the hypothesis of a prominent link between impaired mitophagy and impaired striatal energy homeostasis as a key event in early Parkinson's disease.
    Keywords:   31phosphorus magnetic resonance spectroscopy; Parkinson’s disease; disease stratification; fibroblasts; mitochondria
    DOI:  https://doi.org/10.1093/brain/awad364
  14. Nat Commun. 2023 Dec 02. 14(1): 7991
    Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome.
    Thu Giang Nguyen, Christina Ritter, Eva Kummer.
      Mitochondria contain their own genetic information and a dedicated translation system to express it. The mitochondrial ribosome is assembled from mitochondrial-encoded RNA and nuclear-encoded ribosomal proteins. Assembly is coordinated in the mitochondrial matrix by biogenesis factors that transiently associate with the maturing particle. Here, we present a structural snapshot of a large mitoribosomal subunit assembly intermediate containing 7 biogenesis factors including the GTPases GTPBP7 and GTPBP10. Our structure illustrates how GTPBP10 aids the folding of the ribosomal RNA during the biogenesis process, how this process is related to bacterial ribosome biogenesis, and why mitochondria require two biogenesis factors in contrast to only one in bacteria.
    DOI:  https://doi.org/10.1038/s41467-023-43599-z
  15. Front Cell Dev Biol. 2023 ;11 1307502
    Dynamics of mitochondrial membranes under photo-oxidative stress with high spatiotemporal resolution.
    Vincent Loriette, Alexandra Fragola, Sergei G Kruglik, Susmita Sridhar, Antoine Hubert, François Orieux, Eduardo Sepulveda, Franck Sureau, Stephanie Bonneau.
      In our study, we harnessed an original Enhanced Speed Structured Illumination Microscopy (Fast-SIM) imaging setup to explore the dynamics of mitochondrial and inner membrane ultrastructure under specific photo-oxidation stress induced by Chlorin-e6 and light irradiation. Notably, our Fast-SIM system allowed us to observe and quantify a distinct remodeling and shortening of the mitochondrial structure after 60-80 s of irradiation. These changes were accompanied by fusion events of adjacent inner membrane cristae and global swelling of the organelle. Preceding these alterations, a larger sequence was characterized by heightened dynamics within the mitochondrial network, featuring events such as mitochondrial fission, rapid formation of tubular prolongations, and fluctuations in cristae structure. Our findings provide compelling evidence that, among enhanced-resolution microscopy techniques, Fast-SIM emerges as the most suitable approach for non-invasive dynamic studies of mitochondrial structure in living cells. For the first time, this approach allows quantitative and qualitative characterization of successive steps in the photo-induced oxidation process with sufficient spatial and temporal resolution.
    Keywords:  Chlorin-e6; dynamics; live cell imaging; mitochondria; oxidation; shape changes; structured illumination microscopy (SIM); sub-organelles structures
    DOI:  https://doi.org/10.3389/fcell.2023.1307502
  16. FEBS Lett. 2023 Dec 06.
    Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
    Francesco De Leonardis, Amer Ahmed, Angelo Vozza, Loredana Capobianco, Christopher L Riley, Simona Nicole Barile, Daria Di Molfetta, Stefano Tiziani, John DiGiovanni, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.
      Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient "uncoupled" respiration, including fasting and exercise. Here we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, oxaloacetate, and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.
    Keywords:  amino acid transport; anion transport; bioenergetics; mitochondrial metabolism; mitochondrial transport; uncoupling protein
    DOI:  https://doi.org/10.1002/1873-3468.14784
  17. Cell Cycle. 2023 Dec 05. 1-19
    The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
    Nian-Siou Wu, I-Chu Ma, Yi-Fan Lin, Huey-Jiun Ko, Joon-Khim Loh, Yi-Ren Hong.
      Recent study had deepened our knowledge of the mitochondrial dynamics to classify mitochondrial fission into two types. To further clarify the relationship between the two distinct fission machinery and the four major adaptors of Drp1, we propose a model of mechanism elucidating the multiple functions of phospho-Drp1 with its adaptors during cell cycle and providing in-depth insights into the molecular basis and evolutionary implications in depth. The model highlights not only the clustering characteristics of different phospho-Drp1 with respective subsets of mitochondrial pro-fission adaptors but also the correlation, crosstalk and shifting between different clustering of phosphorylated Drp1-adaptors during different key fission situations. Particularly, phospho-Drp1 (Ser616) couples with Mff/MiD51 to exert mitochondrial division and phospho-Drp1 (Ser637) couples with MiD49/Fis1 to execute mitophagy in M-phase. We then apply the model to address the relationship of mitochondrial dynamics to Parkinson's disease (PD) and carcinogenesis. Our proposed model is indeed compatible with current research results and pathological observations, providing promising directions for future treatment design.
    Keywords:  Drp1; Mitochondrial Adaptors; cell cycle; mitophagy; phosphorylation
    DOI:  https://doi.org/10.1080/15384101.2023.2289753
  18. Skelet Muscle. 2023 Dec 04. 13(1): 20
    Replenishing NAD+ content reduces aspects of striated muscle disease in a dog model of Duchenne muscular dystrophy.
    Déborah Cardoso, Inès Barthélémy, Stéphane Blot, Antoine Muchir.
      Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene and loss of the protein dystrophin, which ultimately leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Among the developed therapeutic strategies for DMD, gene therapy approaches partially restore micro-dystrophin or quasi-dystrophin expression. However, despite extensive attempts to develop definitive therapies for DMD, the standard of care remains corticosteroid, which has only palliative benefits. Animal models have played a key role in studies of DMD pathogenesis and treatment development. The golden retriever muscular dystrophy (GRMD) dog displays a phenotype aligning with the progressive course of DMD. Therefore, canine studies may translate better to humans. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for striated muscle function. We showed here that NAD+ content was decreased in the striated muscles of GRMD, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Moreover, we showed that boosting NAD+ content using nicotinamide (NAM), a natural NAD+ precursor, modestly reduces aspects of striated muscle disease. Collectively, our results provide mechanistic insights into DMD.
    Keywords:  Duchenne muscular dystrophy; GRMD; NAD+; Nicotinamide
    DOI:  https://doi.org/10.1186/s13395-023-00328-w
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