bims-mitdis 2023-12-10 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2023‒12‒10
forty papers selected by
Catalina Vasilescu, Helmholz Munich

Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.
CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality.
Endocrine features of primary mitochondrial diseases.
Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome.
Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.
SDHA Variants Can Only Be Classified as Causative Once Their Pathogenicity Has Been Proven.
Inferring compound heterozygosity from large-scale exome sequencing data.
Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging.
The mystery of phospho-Drp1 with four adaptors in cell cycle: when mitochondrial fission couples to cell fate decisions.
Skeletal muscle mitochondria demonstrate similar respiration per cristae surface area independent of training status and sex in healthy humans.
The contribution of mitochondria to age-related skeletal muscle wasting: A sex-specific perspective.
Multimodal assessment of mitochondrial function in Parkinson's disease.
Recommendations for Risk Allele Evidence Curation, Classification, and Reporting from the ClinGen Low Penetrance/Risk Allele Working Group.
Dynamics of mitochondrial membranes under photo-oxidative stress with high spatiotemporal resolution.
Quantitative assessment of mitochondrial morphology relevant for studies on cellular health and environmental toxicity.
Mitochondrial recruitment in myelin: an anchor for myelin dynamics and plasticity?
Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines.
Response to "Pathogenicity of Variant m.13528A>G in MT-ND5 in Leber's Hereditary Optic Neuropathy Is Unsupported".
MitoTracer facilitates the identification of informative mitochondrial mutations for precise lineage reconstruction.
Long-Term Safety of Systemic Ozone Therapy in a Patient With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS).
A genomic mutational constraint map using variation in 76,156 human genomes.
Neurological presentations of inborn errors of purine and pyrimidine metabolism.
De-risking rare disease acquisitions: a win-win-win for patients, biotech and investors.
Biotin rescues manganese-induced Parkinson's disease phenotypes and neurotoxicity.
The impact of 60 days of -6° head down tilt bed rest on mitochondrial content, respiration and regulators of mitochondrial dynamics.
Selenite ameliorates the ATP hydrolysis of mitochondrial F1FO-ATPase by changing the redox state of thiol groups and impairs the ADP phosphorylation.
An expanded genomic database for identifying disease-related variants.
Mitochondrial Quality Control: Its Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
One-Hour Phosphoproteome Analysis with the Orbitrap Astral Mass Spectrometer.
A new role for phosphoinositides in regulating mitochondrial dynamics.
Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease.
In vivo measurement of mitochondrial ROS production in mouse models of photoreceptor degeneration.
Organ aging signatures in the plasma proteome track health and disease.
Systems levels analysis of lipid metabolism in oxygen-induced retinopathy.
Custom machine learning algorithm for large-scale disease screening - taking heart disease data as an example.
Mitochondria isolated from lipid droplets of white adipose tissue reveal functional differences based on lipid droplet size.
Modeling mitochondria, where are the numbers?
An ex vivo screening using mouse brain mitochondria identified seco-cycline D as an inhibitor of mitochondrial permeability transition pore.
mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
Listening to patients with suspected genetic diagnoses: A narrative perspective.

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
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
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
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
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
Mol Syndromol. 2023 Dec;14(6): 457-458

SDHA Variants Can Only Be Classified as Causative Once Their Pathogenicity Has Been Proven.

Josef Finsterer.



Keywords:  Complex-II; Leigh syndrome; Mitochondrial disorder; Respiratory chain; SDH

DOI:  https://doi.org/10.1159/000531506
Nat Genet. 2023 Dec 06.

Inferring compound heterozygosity from large-scale exome sequencing data.

gnomAD Project Consortium

Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

DOI: https://doi.org/10.1038/s41588-023-01608-3
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
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
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
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
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
Genet Med. 2023 Dec 03. pii: S1098-3600(23)01052-3. [Epub ahead of print] 101036

Recommendations for Risk Allele Evidence Curation, Classification, and Reporting from the ClinGen Low Penetrance/Risk Allele Working Group.

ClinGen Low Penetrance/Risk Allele Working Group

  PURPOSE: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret since their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.METHODS: The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
RESULTS: We formally recognize risk alleles and low penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
CONCLUSION: These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.

Keywords:  Association Studies; Clinical Disease Risk Assessment; Penetrance; Risk Allele; Variant Classification

DOI:  https://doi.org/10.1016/j.gim.2023.101036
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
Comput Struct Biotechnol J. 2023 ;21 5609-5619

Quantitative assessment of mitochondrial morphology relevant for studies on cellular health and environmental toxicity.

Sophie Charrasse, Titouan Poquillon, Charlotte Saint-Omer, Manuela Pastore, Benoit Bordignon, Richard E Frye, Christelle Reynes, Victor Racine, Abdel Aouacheria.

  Mitochondria are essential organelles that play crucial roles in cellular energy metabolism, calcium signaling and apoptosis. Their importance in tissue homeostasis and stress responses, combined to their ability to transition between various structural and functional states, make them excellent organelles for monitoring cellular health. Quantitative assessment of mitochondrial morphology can therefore provide valuable insights into environmentally-induced cell damage. High-content screening (HCS) provides a powerful tool for analyzing organelles and cellular substructures. We developed a fully automated and miniaturized HCS wet-plus-dry pipeline (MITOMATICS) exploiting mitochondrial morphology as a marker for monitoring cellular health or damage. MITOMATICS uses an in-house, proprietary software (MitoRadar) to enable fast, exhaustive and cost-effective analysis of mitochondrial morphology and its inherent diversity in live cells. We applied our pipeline and big data analytics software to assess the mitotoxicity of selected chemicals, using the mitochondrial uncoupler CCCP as an internal control. Six different pesticides (inhibiting complexes I, II and III of the mitochondrial respiratory chain) were tested as individual compounds and five other pesticides present locally in Occitanie (Southern France) were assessed in combination to determine acute mitotoxicity. Our results show that the assayed pesticides exhibit specific signatures when used as single compounds or chemical mixtures and that they function synergistically to impact mitochondrial architecture. Study of environment-induced mitochondrial damage has the potential to open new fields in mechanistic toxicology, currently underexplored by regulatory toxicology and exposome research. Such exploration could inform health policy guidelines and foster pharmacological intervention, water, air and soil pollution control and food safety.

Keywords:  Cellular stress; Confocal microscopy; Environmental health; High content analysis; Live-cell imaging; Mitochondria; Pesticides; Quantitative imaging

DOI:  https://doi.org/10.1016/j.csbj.2023.11.015
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
Elife. 2023 Dec 07. pii: RP89682. [Epub ahead of print]12

Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines.

Connon I Thomas, Melissa A Ryan, Naomi Kamasawa, Benjamin Scholl.

  Postsynaptic mitochondria are critical for the development, plasticity, and maintenance of synaptic inputs. However, their relationship to synaptic structure and functional activity is unknown. We examined a correlative dataset from ferret visual cortex with in vivo two-photon calcium imaging of dendritic spines during visual stimulation and electron microscopy reconstructions of spine ultrastructure, investigating mitochondrial abundance near functionally and structurally characterized spines. Surprisingly, we found no correlation to structural measures of synaptic strength. Instead, we found that mitochondria are positioned near spines with orientation preferences that are dissimilar to the somatic preference. Additionally, we found that mitochondria are positioned near groups of spines with heterogeneous orientation preferences. For a subset of spines with a mitochondrion in the head or neck, synapses were larger and exhibited greater selectivity to visual stimuli than those without a mitochondrion. Our data suggest mitochondria are not necessarily positioned to support the energy needs of strong spines, but rather support the structurally and functionally diverse inputs innervating the basal dendrites of cortical neurons.

Keywords:  Mustela furo; dendrite spine; electron microscopy; mitochondria; neuroscience; two-photon calcium imaging

DOI:  https://doi.org/10.7554/eLife.89682
Case Rep Ophthalmol. 2023 Jan-Dec;14(1):14(1): 665-666

Response to "Pathogenicity of Variant m.13528A>G in MT-ND5 in Leber's Hereditary Optic Neuropathy Is Unsupported".

Bhadra U Pandya, Amir R Vosoughi, Aaditeya Jhaveri, Jonathan A Micieli.

DOI: https://doi.org/10.1159/000535021
bioRxiv. 2023 Nov 22. pii: 2023.11.22.568285. [Epub ahead of print]

MitoTracer facilitates the identification of informative mitochondrial mutations for precise lineage reconstruction.

Xuexin Yu, Jing Hu, Yuhao Tan, Mingyao Pan, Hongyi Zhang, Bo Li.

Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of informative MT mutations. Here, we introduced an open-source computational algorithm called "MitoTracer", which accurately identified clonally informative MT mutations and inferred evolutionary lineage from scRNA-seq or scATAC-seq samples. We benchmarked MitoTracer using the ground-truth experimental lineage sequencing data and demonstrated its superior performance over the existing methods measured by high sensitivity and specificity. MitoTracer is compatible with multiple single cell sequencing platforms. Its application to a cancer evolution dataset revealed the genes related to primary BRAF-inhibitor resistance from scRNA-seq data of BRAF-mutated cancer cells. Overall, our work provided a valuable tool for capturing real informative MT mutations and tracing the lineages among cells.Teaser: MitoTracer enables automatically and accurately discover informative mitochondrial mutations for lineage tracing.

DOI: https://doi.org/10.1101/2023.11.22.568285
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
Nature. 2023 Dec 06.

A genomic mutational constraint map using variation in 76,156 human genomes.

Genome Aggregation Database Consortium

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

DOI: https://doi.org/10.1038/s41586-023-06045-0
Eur J Paediatr Neurol. 2023 Dec 04. pii: S1090-3798(23)00183-6. [Epub ahead of print]48 69-77

Neurological presentations of inborn errors of purine and pyrimidine metabolism.

Marie-Cécile Nassogne, Sandrine Marie, Joseph P Dewulf.

  Purines and pyrimidines are essential components as they are the building blocks of vital molecules, such as nucleic acids, coenzymes, signalling molecules, as well as energy transfer molecules. Purine and pyrimidine metabolism defects are characterised by abnormal concentrations of purines, pyrimidines and/or their metabolites in cells or body fluids. This phenomenon is due to a decreased or an increased activity of enzymes involved in this metabolism and has been reported in humans for over 60 years. This review provides an overview of neurological presentations of inborn errors of purine and pyrimidine metabolism. These conditions can lead to psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscular symptoms. Clinical signs are often nonspecific and thus overlooked, but some diseases are treatable and early diagnosis may improve the child's future. Although these metabolic hereditary diseases are rare, they are most probably under-diagnosed. When confronted with suggestive clinical or laboratory signs, clinicians should prescribe genetic testing in association with a biochemical screening including thorough purine and pyrimidine metabolites analysis and/or specific enzyme evaluation. This is most likely going to increase the number of confirmed patients.

Keywords:  Metabolism defects; Neurological presentations; Purine; Pyrimidine

DOI:  https://doi.org/10.1016/j.ejpn.2023.11.013
Nat Rev Drug Discov. 2023 Dec 06.

De-risking rare disease acquisitions: a win-win-win for patients, biotech and investors.

James A Levine, Clea Stemitsiotis.

DOI: https://doi.org/10.1038/d41573-023-00190-x
bioRxiv. 2023 Nov 21. pii: 2023.11.21.568033. [Epub ahead of print]

Biotin rescues manganese-induced Parkinson's disease phenotypes and neurotoxicity.

Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W Miller, Souvarish Sarkar.

Occupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson's disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying such link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adult Drosophila model of Mn toxicity to recapitulate key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosome and mitochondria. We performed global metabolomics on flies at an early stage of toxicity and identified metabolism of the B vitamin, biotin (vitamin B 7 ), as a master pathway underpinning Mn toxicity with systemic, body-brain increases in Mn-treated groups compared to the controls. Using Btnd RNAi mutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction; while in Mn-exposed wild-type flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)- differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated circulating levels of biotin transporters but not of metabolic enzymes compared to healthy controls, suggesting humoral biotin transport as a key event involved in PD. Taken together, our findings identified compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and parkinsonian pathology, providing new basis for devising effective countermeasures against manganism and PD.Significance Statement: Environmental exposure to manganese (Mn) may increase the risk for Parkinson's disease (PD); however, the mechanistic basis linking the two remains unclear. Our adult fruit fly ( Drosophila ) model of Mn toxicity recapitulated key Parkinson's hallmarks in vivo spanning behavioral deficits, neuronal loss, and mitochondrial dysfunction. Metabolomics identified the biotin (vitamin B 7 ) pathway as a key mediator, featuring systemic biotin increases in the flies. Rescue trials leveraging biotin-deficient flies, wild-type flies, and human iPSC-derived dopaminergic neurons determined biotin as a driver of manganism, with the parkinsonian phenotypes dramatically reversed through biotin supplementation. Our findings, in line with overexpressed circulating biotin transporters observed in PD patients, suggest compensatory biotin pathway as a key to untangle the Mn-PD link for combating neurodegenerative disease.

DOI: https://doi.org/10.1101/2023.11.21.568033
J Physiol. 2023 Dec 04.

The impact of 60 days of -6° head down tilt bed rest on mitochondrial content, respiration and regulators of mitochondrial dynamics.

John Noone, Anthony Damiot, Helena Kenny, Isabelle Chery, Alexandre Zahariev, Sylvie Normand, François Crampes, Isabelle de Glisezinski, Keith D Rochfort, Claire Laurens, Marie-Pierre Bareille, Chantal Simon, Audrey Bergouignan, Stéphane Blanc, Donal J O'Gorman.

  It is unclear how skeletal muscle metabolism and mitochondrial function adapt to long duration bed rest and whether changes can be prevented by nutritional intervention. The present study aimed (1) to assess the effect of prolonged bed rest on skeletal muscle mitochondrial function and dynamics and (2) to determine whether micronutrient supplementation would mitigate the adverse metabolic effect of bed rest. Participants were maintained in energy balance throughout 60 days of bed rest with micronutrient supplementation (INT) (body mass index: 23.747 ± 1.877 kg m-2 ; 34.80 ± 7.451 years; n = 10) or without (control) (body mass index: 24.087 ± 2.088 kg m-2 ; 33.50 ± 8.541 years; n = 10). Indirect calorimetry and dual-energy x-ray absorptiometry were used for measures of energy expenditure, exercise capacity and body composition. Mitochondrial respiration was determined by high-resolution respirometry in permeabilized muscle fibre bundles from vastus lateralis biopsies. Protein and mRNA analysis further examined the metabolic changes relating to regulators of mitochondrial dynamics induced by bed rest. INT was not sufficient in preserving whole body metabolic changes conducive of a decrease in body mass, fat-free mass and exercise capacity within both groups. Mitochondrial respiration, OPA1 and Drp1 protein expression decreased with bed rest, with an increase pDrp1s616 . This reduction in mitochondrial respiration was explained through an observed decrease in mitochondrial content (mtDNA:nDNA). Changes in regulators of mitochondrial dynamics indicate an increase in mitochondrial fission driven by a decrease in inner mitochondrial membrane fusion (OPA1) and increased pDrp1s616 . KEY POINTS: Sixty days of -6° head down tilt bed rest leads to significant changes in body composition, exercise capacity and whole-body substrate metabolism. Micronutrient supplementation throughout bed rest did not preserve whole body metabolic changes. Bed rest results in a decrease in skeletal muscle mitochondrial respiratory capacity, mainly as a result of an observed decrease in mitochondrial content. Prolonged bed rest ensues changes in key regulators of mitochondrial dynamics. OPA1 and Drp1 are significantly reduced, with an increase in pDrp1s616 following bed rest indicative of an increase in mitochondrial fission. Given the reduction in mitochondrial content following 60 days of bed rest, the maintenance of regulators of mitophagy in line with the increase in regulators of mitochondrial fission may act to maintain mitochondrial respiration to meet energy demands.

Keywords:  OPA1; bed rest; energy expenditure; metabolism; mitochondrial dynamics; mitochondrial function; skeletal muscle

DOI:  https://doi.org/10.1113/JP284734
Free Radic Biol Med. 2023 Dec 04. pii: S0891-5849(23)01142-5. [Epub ahead of print]

Selenite ameliorates the ATP hydrolysis of mitochondrial F1FO-ATPase by changing the redox state of thiol groups and impairs the ADP phosphorylation.

Cristina Algieri, Francesca Oppedisano, Fabiana Trombetti, Micaela Fabbri, Ernesto Palma, Salvatore Nesci.

  Selenite as an inorganic form of selenium can affect the redox state of mitochondria by modifying the thiol groups of cysteines. The F1FO-ATPase has been identified as a mitochondrial target of this compound. Indeed, the bifunctional mechanism of ATP turnover of F1FO-ATPase was differently modified by selenite. The activity of ATP hydrolysis was stimulated, whereas the ADP phosphorylation was inhibited. We ascertain that a possible new protein adduct identified as seleno-dithiol (-S-Se-S-) mercaptoethanol-sensitive caused the activation of F-ATPase activity and the oxidation of free -SH groups in mitochondria. Conversely, the inhibition of ATP synthesis by selenite might be irreversible. The kinetic analysis of the activation mechanism was an uncompetitive mixed type with respect to the ATP substrate. Selenite bound more selectively to the F1FO-ATPase loaded with the substrate by preferentially forming a tertiary (enzyme-ATP-selenite) complex. Otherwise, the selenite was a competitive mixed-type activator with respect to the Mg2+ cofactor. Thus, selenite more specifically bound to the free enzyme forming the complex enzyme-selenite. However, even if the selenite impaired the catalysis of F1FO-ATPase, the mitochondrial permeability transition pore phenomenon was unaffected. Therefore, the reversible energy transduction mechanism of F1FO-ATPase can be oppositely regulated by selenite.

Keywords:  F(1)F(O)-ATPase; Mitochondria; Oxidative phosphorylation; Selenite; Thiol groups

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.041
Nature. 2023 Dec 06.

An expanded genomic database for identifying disease-related variants.

Ryan S Dhindsa, Slavé Petrovski.



Keywords:  Genetics; Genomics

DOI:  https://doi.org/10.1038/d41586-023-01598-6
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
bioRxiv. 2023 Nov 21. pii: 2023.11.21.568149. [Epub ahead of print]

One-Hour Phosphoproteome Analysis with the Orbitrap Astral Mass Spectrometer.

Noah M Lancaster, Pavel Sinitcyn, Patrick Forny, Trenton M Peters-Clarke, Caroline Fecher, Andrew J Smith, Evgenia Shishkova, Tabiwang N Arrey, Anna Pashkova, Margaret Lea Robinson, Nicholas Arp, Jing Fan, Juli Hansen, Andrea Galmozzi, Lia R Serrano, Michael S Westphall, Hamish Stewart, Christian Hock, Eugen Damoc, David J Pagliarini, Vlad Zabrouskov, Joshua J Coon.

As a key mechanism for cellular signal transduction, protein phosphorylation plays critical roles in myriad cellular processes. This modification, however, is highly dynamic and occurs at sub-stoichiometric levels. Mass spectrometry is an essential tool for studying this modification on a global scale; however, the technology's impact suffers from four main limitations: need for site localization, dynamic range, reproducibility, and throughput. Here we describe the use of a novel mass spectrometer (Orbitrap Astral) coupled with data-independent acquisition (DIA) to achieve detection of close to 40,000 unique phosphorylation sites within one hour of analysis. We applied this approach to generate a phosphoproteome atlas of the mouse. Altogether, we detected 81,120 unique phosphorylation sites within 12 hours of measurement. With this unique dataset, we examine the sequence and structural context of protein phosphorylation. Finally, we highlight the discovery potential of this resource with multiple examples of novel phosphorylation events relevant to mitochondrial and brain biology.

DOI: https://doi.org/10.1101/2023.11.21.568149
Adv Biol Regul. 2023 Nov 30. pii: S2212-4926(23)00047-7. [Epub ahead of print] 101001

A new role for phosphoinositides in regulating mitochondrial dynamics.

Sonia Raveena Lourdes, Rajendra Gurung, Saveen Giri, Christina A Mitchell, Meagan J McGrath.

  Phosphoinositides are a minor group of membrane-associated phospholipids that are transiently generated on the cytoplasmic leaflet of many organelle membranes and the plasma membrane. There are seven functionally distinct phosphoinositides, each derived via the reversible phosphorylation of phosphatidylinositol in various combinations on the inositol ring. Their generation and termination is tightly regulated by phosphatidylinositol-kinases and -phosphatases. These enzymes can function together in an integrated and coordinated manner, whereby the phosphoinositide product of one enzyme may subsequently serve as a substrate for another to generate a different phosphoinositide species. This regulatory mechanism not only enables the transient generation of phosphoinositides on membranes, but also more complex sequential or bidirectional conversion pathways, and phosphoinositides can also be transferred between organelles via membrane contacts. It is this capacity to fine-tune phosphoinositide signals that makes them ideal regulators of membrane organization and dynamics, through their recruitment of signalling, membrane altering and lipid transfer proteins. Research spanning several decades has provided extensive evidence that phosphoinositides are major gatekeepers of membrane organization, with roles in endocytosis, exocytosis, autophagy, lysosome dynamics, vesicular transport and secretion, cilia, inter-organelle membrane contact, endosome maturation and nuclear function. By contrast, there has been remarkably little known about the role of phosphoinositides at mitochondria - an enigmatic and major knowledge gap, with challenges in reliably detecting phosphoinositides at this site. Here we review recent significant breakthroughs in understanding the role of phosphoinositides in regulating mitochondrial dynamics and metabolic function.

Keywords:  Mitochondria; Mitochondrial fission; PI(4,5)P(2); PI3P; PI4P; Phosphoinositide

DOI:  https://doi.org/10.1016/j.jbior.2023.101001
Neural Regen Res. 2024 Jul 01. 19(7): 1593-1601

Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease.

Bo Li, Yujie Chen, Yan Zhou, Xuanran Feng, Guojun Gu, Shuang Han, Nianhao Cheng, Yawen Sun, Yiming Zhang, Jiahui Cheng, Qi Zhang, Wei Zhang, Jianhui Liu.

DOI: https://doi.org/10.4103/1673-5374.385839
Redox Biochem Chem. 2023 Dec;5-6 None

In vivo measurement of mitochondrial ROS production in mouse models of photoreceptor degeneration.

Katja E Menger, Angela Logan, Ulrich F O Luhmann, Alexander J Smith, Alan F Wright, Robin R Ali, Michael P Murphy.

  Retinitis pigmentosa (RP) is a disease characterised by photoreceptor cell death. It can be initiated by mutations in a number of different genes, primarily affecting rods, which will die first, resulting in loss of night vision. The secondary death of cones then leads to loss of visual acuity and blindness. We set out to investigate whether increased mitochondrial reactive oxygen species (ROS) formation, plays a role in this sequential photoreceptor degeneration. To do this we measured mitochondrial H2O2 production within mouse eyes in vivo using the mass spectrometric probe MitoB. We found higher levels of mitochondrial ROS that preceded photoreceptor loss in four mouse models of RP: Pde6brd1/rd1; Prhp2rds/rds; RPGR-/-; Cln6nclf. In contrast, there was no increase in mitochondrial ROS in loss of function models of vision loss (GNAT-/-, OGC), or where vision loss was not due to photoreceptor death (Cln3). Upregulation of Nrf2 transcriptional activity with dimethylfumarate (DMF) lowered mitochondrial ROS in RPGR-/- mice. These findings have important implications for the mechanism and treatment of RP.

Keywords:  Mitochondria: hydrogen peroxide; Photoreceptor; Retinitis pigmentosa: MitoB

DOI:  https://doi.org/10.1016/j.rbc.2023.100007
Nature. 2023 Dec;624(7990): 164-172

Organ aging signatures in the plasma proteome track health and disease.

Hamilton Se-Hwee Oh, Jarod Rutledge, Daniel Nachun, Róbert Pálovics, Olamide Abiose, Patricia Moran-Losada, Divya Channappa, Deniz Yagmur Urey, Kate Kim, Yun Ju Sung, Lihua Wang, Jigyasha Timsina, Dan Western, Menghan Liu, Pat Kohlfeld, John Budde, Edward N Wilson, Yann Guen, Taylor M Maurer, Michael Haney, Andrew C Yang, Zihuai He, Michael D Greicius, Katrin I Andreasson, Sanish Sathyan, Erica F Weiss, Sofiya Milman, Nir Barzilai, Carlos Cruchaga, Anthony D Wagner, Elizabeth Mormino, Benoit Lehallier, Victor W Henderson, Frank M Longo, Stephen B Montgomery, Tony Wyss-Coray.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

DOI: https://doi.org/10.1038/s41586-023-06802-1
bioRxiv. 2023 Nov 30. pii: 2023.11.21.568200. [Epub ahead of print]

Systems levels analysis of lipid metabolism in oxygen-induced retinopathy.

Charandeep Singh.

Hyperoxia induces glutamine-fueled anaplerosis in the Muller cells, endothelial cells, and retinal explants. Anaplerosis takes away glutamine from the biosynthetic pathway to the energy-producing TCA cycle. This process depletes biosynthetic precursors from newly proliferating endothelial cells. The induction of anaplerosis in the hyperoxic retina is a compensatory response, either to decreased glycolysis or decreased flux from glycolysis to the TCA cycle. We hypothesized that by providing substrates that feed into TCA, we could reverse or prevent glutamine-fueled anaplerosis, thereby abating the glutamine wastage for energy generation. Using an oxygen-induced retinopathy (OIR) mouse model, we first compared the difference in fatty acid metabolism between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains to understand if these strains exhibit metabolic difference that protects BALB/cByJ from the hyperoxic conditions and prevents their vasculature in oxygen-induced retinopathy model. Based on our findings from the metabolic comparison between two mouse strains, we hypothesized that the medium-chain fatty acid, octanoate, can feed into the TCA and serve as an alternative energy source in response to hyperoxia. Our systems levels analysis of OIR model shows that the medium chain fatty acid can serve as an alternative source to feed TCA. We here, for the first time, demonstrate that the retina can use medium-chain fatty acid octanoate to replenish TCA in normoxic and at a higher rate in hyperoxic conditions.

DOI: https://doi.org/10.1101/2023.11.21.568200
Artif Intell Med. 2023 Dec;pii: S0933-3657(23)00202-6. [Epub ahead of print]146 102688

Custom machine learning algorithm for large-scale disease screening - taking heart disease data as an example.

Leran Chen, Ping Ji, Yongsheng Ma, Yiming Rong, Jingzheng Ren.

  Heart disease accounts for millions of deaths worldwide annually, representing a major public health concern. Large-scale heart disease screening can yield significant benefits both in terms of lives saved and economic costs. In this study, we introduce a novel algorithm that trains a patient-specific machine learning model, aligning with the real-world demands of extensive disease screening. Customization is achieved by concentrating on three key aspects: data processing, neural network architecture, and loss function formulation. Our approach integrates individual patient data to bolster model accuracy, ensuring dependable disease detection. We assessed our models using two prominent heart disease datasets: the Cleveland dataset and the UC Irvine (UCI) combination dataset. Our models showcased notable results, achieving accuracy and recall rates beyond 95 % for the Cleveland dataset and surpassing 97 % accuracy for the UCI dataset. Moreover, in terms of medical ethics and operability, our approach outperformed traditional, general-purpose machine learning algorithms. Our algorithm provides a powerful tool for large-scale disease screening and has the potential to save lives and reduce the economic burden of heart disease.

Keywords:  Attention; Custom model; Customized machine learning; Data augmentation; Disease diagnosis; Heart disease; Large-scale disease screening; Machine learning; Parameter optimization

DOI:  https://doi.org/10.1016/j.artmed.2023.102688
Life Sci Alliance. 2024 Feb;pii: e202301934. [Epub ahead of print]7(2):

Mitochondria isolated from lipid droplets of white adipose tissue reveal functional differences based on lipid droplet size.

Alexandra J Brownstein, Michaela Veliova, Rebeca Acin-Perez, Frankie Villalobos, Anton Petcherski, Alberto Tombolato, Marc Liesa, Orian S Shirihai.

Recent studies in brown adipose tissue (BAT) described a unique subpopulation of mitochondria bound to lipid droplets (LDs), which were termed PeriDroplet Mitochondria (PDM). PDM can be isolated from BAT by differential centrifugation and salt washes. Contrary to BAT, this approach has so far not led to the successful isolation of PDM from white adipose tissue (WAT). Here, we developed a method to isolate PDM from WAT with high yield and purity by an optimized proteolytic treatment that preserves the respiratory function of mitochondria. Using this approach, we show that, contrary to BAT, WAT PDM have lower respiratory and ATP synthesis capacities compared with WAT cytoplasmic mitochondria (CM). Furthermore, by isolating PDM from LDs of different sizes, we found a negative correlation between LD size and the respiratory capacity of their PDM in WAT. Thus, our new isolation method reveals tissue-specific characteristics of PDM and establishes the existence of heterogeneity in PDM function determined by LD size.

DOI: https://doi.org/10.26508/lsa.202301934
Neural Regen Res. 2024 Jul 01. 19(7): 1435-1436

Modeling mitochondria, where are the numbers?

Adrian M Davies, Alan G Holt.

DOI: https://doi.org/10.4103/1673-5374.386402
Biochem Biophys Res Commun. 2023 Nov 20. pii: S0006-291X(23)01347-5. [Epub ahead of print]691 149253

An ex vivo screening using mouse brain mitochondria identified seco-cycline D as an inhibitor of mitochondrial permeability transition pore.

Mie Kubota-Sakashita, Hirochika Kawakami, Ko Kikuzato, Fumiyuki Shirai, Takemichi Nakamura, Tadafumi Kato.

  Mitochondrial dysfunction is implicated in neuropsychiatric disorders. Inhibition of mitochondrial permeability transition pore (mPTP) and thereby enhancement of mitochondrial Ca2+ retention capacity (CRC) is a promising treatment strategy. Here, we screened 1718 compounds to search for drug candidates inhibiting mPTP by measuring their effects on CRC in mitochondria isolated from mouse brains. We identified seco-cycline D (SCD) as an active compound. SCD and its derivative were more potent than a known mPTP inhibitor, cyclosporine A (CsA). The mechanism of action of SCD was suggested likely to be different from CsA that acts on cyclophilin D. Repeated administration of SCD decreased ischemic area in a middle cerebral artery occlusion model in mice. These results suggest that SCD is a useful probe to explore mPTP function.

Keywords:  Calcium; Mitochondria; Mitochondrial permeability transition pore; Neuropsychiatric disorders; Seco-cycline D

DOI:  https://doi.org/10.1016/j.bbrc.2023.149253
Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00417-5. [Epub ahead of print]35(12): 2097-2099

mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.

Estela Jacinto.

Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination.

DOI: https://doi.org/10.1016/j.cmet.2023.11.006
Am J Med Genet C Semin Med Genet. 2023 Dec 04. e32079

Listening to patients with suspected genetic diagnoses: A narrative perspective.

Robert B Slocum, Anna C E Hurst, Ellis Shelley, Lisa Berry, Robert J Hopkin, Alyssa L Rippert, Elizabeth Bhoj, John M Graham, Katheryn Grand, Aixa Gonzalez, Yuri A Zarate.



Keywords:  diagnostic odyssey; narrative medicine; online health information search; patient-provider alliance; rare diseases

DOI:  https://doi.org/10.1002/ajmg.c.32079