bims-mitdis 2023-07-23 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2023–07–23
forty-four papers selected by
Catalina Vasilescu, Helmholz Munich

Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.
Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.
The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).
The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG-related disorders.
ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.
Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement.
Clinical, neuroradiological and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.
Mitochondrial DNA 13513G>A Mutation Causing Leber Hereditary Optic Neuropathy Associated With Adult-Onset Renal Failure.
MOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters.
Mitochondria during T cell aging.
Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.
Hypoxia-induced mitochondrial stress granules.
Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.
Mitochondrial depletion syndrome type 3: the Lebanese variant.
Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation.
Our current understanding of the toxicity of altered mito-ribosomal fidelity during mitochondrial protein synthesis: What can it tell us about human disease?
The emerging significance of mitochondrial targeted strategies in NAFLD treatment.
Broadening the Spectrum of SLC22A5 Phenotype: Primary Carnitine Deficiency Presenting with Focal Myoclonus.
Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.
Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions.
Using Live Cell STED Imaging to Visualize Mitochondrial Inner Membrane Ultrastructure in Neuronal Cell Models.
Medium-chain fatty acid oxidation is independent of L-carnitine in liver and kidney but not in heart and skeletal muscle.
Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens.
FDX1 regulates cellular protein lipoylation through direct binding to LIAS.
Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.
A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.
Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP).
What is really known about the effects of nicotinamide riboside supplementation in humans.
Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery.
Nutritional approaches targeting mitochondria for the prevention of sarcopenia.
Investigating the dark-side of the genome: a barrier to human disease variant discovery?
Design, Synthesis, and Biological Evaluation of Novel Mitochondria-targeting Exosomes.
RDBridge: a knowledge graph of rare diseases based on large-scale text mining.
Quantum sensors: detect heart disease sooner.
Structure-based network analysis predicts mutations associated with inherited retinal disease.
A way forward for diagnosis of patients with extremely rare genetic mutations.
Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.
Detecting disease association with rare variants using weighted entropy.
Child Neurology: Progressive Cerebellar Atrophy and Retinal Dystrophy - Clues to an Ultra-Rare ACO2-Related Neurometabolic Diagnosis.
Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.

Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2210599120

Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.

Svetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Xiaonan Liu, Sundar Baral, Kaneez Fatima, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa.

  Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here, we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from the GRPEL2 locus on a tightly regulated low level. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling and immunoprecipitation analysis suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. Furthermore, NERCLIN is responsive to heat stress ensuring OPA1 processing and cell survival. Thus, we propose that NERCLIN contributes to the stress-induced adaptation of mitochondrial dynamics. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.

Keywords:  NERCLIN; OPA1; cardiolipin; prohibitins; small mitochondrial proteins

DOI:  https://doi.org/10.1073/pnas.2210599120
Front Genet. 2023 ;14 1089956

Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.

Chiara Frascarelli, Nadia Zanetti, Alessia Nasca, Rossella Izzo, Costanza Lamperti, Eleonora Lamantea, Andrea Legati, Daniele Ghezzi.

  Primary mitochondrial diseases are progressive genetic disorders affecting multiple organs and characterized by mitochondrial dysfunction. These disorders can be caused by mutations in nuclear genes coding proteins with mitochondrial localization or by genetic defects in the mitochondrial genome (mtDNA). The latter include point pathogenic variants and large-scale deletions/rearrangements. MtDNA molecules with the wild type or a variant sequence can exist together in a single cell, a condition known as mtDNA heteroplasmy. MtDNA single point mutations are typically detected by means of Next-Generation Sequencing (NGS) based on short reads which, however, are limited for the identification of structural mtDNA alterations. Recently, new NGS technologies based on long reads have been released, allowing to obtain sequences of several kilobases in length; this approach is suitable for detection of structural alterations affecting the mitochondrial genome. In the present work we illustrate the optimization of two sequencing protocols based on long-read Oxford Nanopore Technology to detect mtDNA structural alterations. This approach presents strong advantages in the analysis of mtDNA compared to both short-read NGS and traditional techniques, potentially becoming the method of choice for genetic studies on mtDNA.

Keywords:  MinION; complex-rearrangements; long reads; macrodeletion; mtDNA; multiple deletions; oxford nanopore; structural variants

DOI:  https://doi.org/10.3389/fgene.2023.1089956
bioRxiv. 2023 Jul 07. pii: 2023.07.07.548169. [Epub ahead of print]

Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.

Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes.

Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.
SUMMARY: Wilson and colleagues use electron tomography and time-lapse fluorescence microscopy to observe that mitochondrial-derived compartments (MDCs) are generated from outer mitochondrial membrane extensions that repeatedly elongate, coalesce, and invaginate to secure membrane cargo and cytosol within a distinct, protected domain.

DOI: https://doi.org/10.1101/2023.07.07.548169
Geroscience. 2023 Jul 18.

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).

Gavin Pharaoh, Varun Kamat, Sricharan Kannan, Rudolph S Stuppard, Jeremy Whitson, Miguel Martín-Pérez, Wei-Jun Qian, Michael J MacCoss, Judit Villén, Peter Rabinovitch, Matthew D Campbell, Ian R Sweet, David J Marcinek.

  Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H+ (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2 (flavin adenine dinucleotide), O2 (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).

Keywords:  ATP production; Adenine nucleotide translocator (ANT); Adenosine diphosphate (ADP) sensitivity; Elamipretide or SS-31; Mitochondrial dysfunction; Oxygen consumption rate (OCR)

DOI:  https://doi.org/10.1007/s11357-023-00861-y
IUBMB Life. 2023 Jul 20.

The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG-related disorders.

Alexandru Ionut Gilea, Martina Magistrati, Ilenia Notaroberto, Natascia Tiso, Cristina Dallabona, Enrico Baruffini.

  Most eukaryotes possess a mitochondrial genome, called mtDNA. In animals and fungi, the replication of mtDNA is entrusted by the DNA polymerase γ, or Pol γ. The yeast Pol γ is composed only of a catalytic subunit encoded by MIP1. In humans, Pol γ is a heterotrimer composed of a catalytic subunit homolog to Mip1, encoded by POLG, and two accessory subunits. In the last 25 years, more than 300 pathological mutations in POLG have been identified as the cause of several mitochondrial diseases, called POLG-related disorders, which are characterized by multiple mtDNA deletions and/or depletion in affected tissues. In this review, at first, we summarize the biochemical properties of yeast Mip1, and how mutations, especially those introduced recently in the N-terminal and C-terminal regions of the enzyme, affect the in vitro activity of the enzyme and the in vivo phenotype connected to the mtDNA stability and to the mtDNA extended and point mutability. Then, we focus on the use of yeast harboring Mip1 mutations equivalent to the human ones to confirm their pathogenicity, identify the phenotypic defects caused by these mutations, and find both mechanisms and molecular compounds able to rescue the detrimental phenotype. A closing chapter will be dedicated to other polymerases found in yeast mitochondria, namely Pol ζ, Rev1 and Pol η, and to their genetic interactions with Mip1 necessary to maintain mtDNA stability and to avoid the accumulation of spontaneous or induced point mutations.

Keywords:  DNA polymerase γ; DNA polymerase ζ-Rev1; DNA polymerase η; Mip1; POLG-related disorders; yeast

DOI:  https://doi.org/10.1002/iub.2770
Nat Cell Biol. 2023 Jul 17.

ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.

Chuan-Yang Dai, Chai Chee Ng, Grace Ching Ching Hung, Ina Kirmes, Laetitia A Hughes, Yunguang Du, Christopher A Brosnan, Arnaud Ahier, Anne Hahn, Cole M Haynes, Oliver Rackham, Aleksandra Filipovska, Steven Zuryn.

The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.

DOI: https://doi.org/10.1038/s41556-023-01192-y
J Clin Invest. 2023 07 17. pii: e171965. [Epub ahead of print]133(14):

Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?

Abhinav Diwan.

Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.

DOI: https://doi.org/10.1172/JCI171965
Biochim Biophys Acta Mol Basis Dis. 2023 Jul 14. pii: S0925-4439(23)00174-6. [Epub ahead of print] 166808

SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement.

Elianne P Bulthuis, Merel J W Adjobo-Hermans, Bastiaan de Potter, Saskia Hoogstraten, Lisanne H T Wezendonk, Omar A Z Tutakhel, Liesbeth T Wintjes, Bert van den Heuvel, Peter H G M Willems, Erik-Jan Kamsteeg, M Estela Rubio Gozalbo, Suzanne C E H Sallevelt, Suzanne M Koudijs, Joost Nicolai, Charlotte I de Bie, Jessica E Hoogendijk, Werner J H Koopman, Richard J Rodenburg.

  Ionic calcium (Ca2+) is a key messenger in signal transduction and its mitochondrial uptake plays an important role in cell physiology. This uptake is mediated by the mitochondrial Ca2+ uniporter (MCU), which is regulated by EMRE (essential MCU regulator) encoded by the SMDT1 (single-pass membrane protein with aspartate rich tail 1) gene. This work presents the genetic, clinical and cellular characterization of two patients harbouring SMDT1 variants and presenting with muscle problems. Analysis of patient fibroblasts and complementation experiments demonstrated that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+ uptake. However, the activity of the oxidative phosphorylation enzymes, mitochondrial morphology and membrane potential, as well as routine/ATP-linked respiration were not affected. We hypothesize that the muscle-related symptoms in the SMDT1 patients result from aberrant mitochondrial Ca2+ uptake.

Keywords:  Calcium; EMRE; MCU; Mitochondria; Muscle involvement; SMDT1

DOI:  https://doi.org/10.1016/j.bbadis.2023.166808
Genet Med. 2023 Jul 13. pii: S1098-3600(23)00951-6. [Epub ahead of print] 100938

Clinical, neuroradiological and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.

Andrea Accogli, Sheng-Jia Lin, Mariasavina Severino, Sung-Hoon Kim, Kevin Huang, Clarissa Rocca, Megan Landsverk, Maha Zaki, Almundher Al-Maawali, Varunvenkat M Srinivasan, Khalid Al-Thihli, G Bradly Schaefer, Monica Davis, Davide Tonduti, Chiara Doneda, Lara M Marten, Chris Mühlhausen, Maria Gomez, Eleonora Lamantea, Rafael Mena, Mathilde Nizon, Vincent Procaccio, Amber Begtrup, Aida Telegrafi, Hong Cui, Heidi L Schulz, Julia Mohr, Saskia Biskup, Mariana Amina Loos, Hilda Verónica Aráoz, Vincenzo Salpietro, Laura Davis Keppen, Manali Chitre, Cassidy Petree, Lucy Raymond, Julie Vogt, Lindsey B Swayer, Alice A Basinger, Signe Vandal Pedersen, Toni S Pearson, Dorothy K Grange, Lokesh Lingapp, Paige McDunnah, Rita Horvath, Benjamin Cogne, Bertrand Isidor, Andreas Hahn, Karen Gripp, Seyed Mehdi Jafarnejad, Elsebet Ostergaard, Carlos E Prada, Daniele Ghezzi, Vykuntaraju K Gowda, Robert W Taylor, Nahum Sonenberg, Henry Houlden, Marie Sissler, Gaurav K Varshney, Reza Maroofian.

   PURPOSE: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype, but with limited neuroradiological data and insufficient evidence for causality of the variants.
METHODS: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays, and a zebrafish model.
RESULTS: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model.
CONCLUSION: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.

Keywords:  TARS2; cerebellar atrophy; mTORC1 signaling; mitochondrial dysfunction; mitochondrial threonyl-tRNA-synthetase; white matter

DOI:  https://doi.org/10.1016/j.gim.2023.100938
J Neuroophthalmol. 2023 Jul 21.

Mitochondrial DNA 13513G>A Mutation Causing Leber Hereditary Optic Neuropathy Associated With Adult-Onset Renal Failure.

Grace Swart, Clare L Fraser, Meena Shingde, Elizabeth O Thompson, Amali Mallawaarachchi, Mitchell Lawlor, Kate Ahmad, Gabor M Halmagyi.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is one of the more common mitochondrial diseases and is rarely associated with mitochondrial renal disease. We report 3 unrelated patients with a background of adult-onset renal failure who presented to us with LHON and were shown to have a heteroplasmic mitochondrial DNA mutation (m.13513G>A).
METHODS: Retrospective chart review.
RESULTS: All 3 patients had a background of chronic renal failure and presented to us with bilateral optic neuropathy (sequential in 2) and were found to have heteroplasmic m.13513G>A mutations in the MT-ND5 gene. Two of the patients were females (aged 30 and 45 years) with chronic kidney disease from their 20s, attributed to pre-eclampsia, one of whom also had diabetes and sudden bilateral hearing loss. One patient was a male (aged 54 years) with chronic kidney disease from his 20s attributed to IgA nephropathy. His mother had diabetes and apparently sudden bilateral blindness in her 70s. Renal biopsy findings were variable and included interstitial fibrosis, acute tubular necrosis, focal segmental glomerulosclerosis, and IgA/C3 tubular casts on immunofluorescence. Mild improvements in vision followed treatment with either idebenone or a combination supplement including coenzyme Q10, alpha-lipoic acid, and B vitamins.
CONCLUSIONS: Our cases expand the clinical syndromes associated with m.13513G>A to include bilateral optic neuropathy and adult-onset renal disease. This highlights that in patients with bilateral, especially sequential, optic neuropathy a broad approach to mitochondrial testing is more useful than a limited LHON panel. Mitochondrial diseases present a diagnostic challenge because of their clinical and genetic variability.

DOI: https://doi.org/10.1097/WNO.0000000000001946
Nat Commun. 2023 Jul 21. 14(1): 4404

MOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters.

Dongmei Wang, Haimin Li, Navdeep S Chandel, Yali Dou, Rui Yi.

Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in controlling cellular function and regulating mammalian tissue development remain unclear. Here we show that conditional deletion of Mof in the skin, but not Kansl1, causes severe defects in the self-renewal of basal epithelial progenitors, epidermal differentiation, and hair follicle growth, resulting in barrier defects and perinatal lethality. MOF-regulated genes are highly enriched for essential functions in the mitochondria and cilia. Genetic deletion of Uqcrq, an essential subunit for the electron transport chain (ETC) Complex III, in the skin, recapitulates the defects in epidermal differentiation and hair follicle growth observed in MOF knockout mouse. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for regulating mitochondrial and ciliary gene expression and underscores the important function of the MOF/ETC axis for mammalian skin development.

DOI: https://doi.org/10.1038/s41467-023-40108-0
Semin Immunol. 2023 Jul 18. pii: S1044-5323(23)00099-4. [Epub ahead of print]69 101808

Mitochondria during T cell aging.

Jose Ignacio Escrig-Larena, Sandra Delgado-Pulido, María Mittelbrunn.

  Mitochondrial dysfunction is a hallmark of aging that contributes to inflammaging. It is characterized by alterations of the mitochondrial DNA, reduced respiratory capacity, decreased mitochondrial membrane potential and increased reactive oxygen species production. These primary alterations disrupt other interconnected and important mitochondrial-related processes such as metabolism, mitochondrial dynamics and biogenesis, mitophagy, calcium homeostasis or apoptosis. In this review, we gather the current knowledge about the different mitochondrial processes which are altered during aging, with special focus on their contribution to age-associated T cell dysfunction and inflammaging.

Keywords:  Aging; Apoptosis; Calcium homeostasis; Inflammaging; Lymphocyte; Mitochondria; Mitochondrial dynamics; Mitokines; Mitophagy; MtDNA; ROS; T cells

DOI:  https://doi.org/10.1016/j.smim.2023.101808
Cell Metab. 2023 Jul 14. pii: S1550-4131(23)00225-5. [Epub ahead of print]

Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.

Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver.

  Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.

Keywords:  brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil

DOI:  https://doi.org/10.1016/j.cmet.2023.06.015
Sci Adv. 2023 Jul 21. 9(29): eadh3347

Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.

Wesley Peng, Leonie F Schröder, Pingping Song, Yvette C Wong, Dimitri Krainc.

Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson's disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.

DOI: https://doi.org/10.1126/sciadv.adh3347
Cell Death Dis. 2023 Jul 19. 14(7): 448

Hypoxia-induced mitochondrial stress granules.

Chun-Ling Sun, Marc Van Gilst, C Michael Crowder.

Perturbations of mitochondrial proteostasis have been associated with aging, neurodegenerative diseases, and recently with hypoxic injury. While examining hypoxia-induced mitochondrial protein aggregation in C. elegans, we found that sublethal hypoxia, sodium azide, or heat shock-induced abundant ethidium bromide staining mitochondrial granules that preceded evidence of protein aggregation. Genetic manipulations that reduce cellular and organismal hypoxic death block the formation of these mitochondrial stress granules (mitoSG). Knockdown of mitochondrial nucleoid proteins also blocked the formation of mitoSG by a mechanism distinct from the mitochondrial unfolded protein response. Lack of the major mitochondrial matrix protease LONP-1 resulted in the constitutive formation of mitoSG without external stress. Ethidium bromide-staining RNA-containing mitochondrial granules were also observed in rat cardiomyocytes treated with sodium azide, a hypoxia mimetic. Mitochondrial stress granules are an early mitochondrial pathology controlled by LONP and the nucleoid, preceding hypoxia-induced protein aggregation.

DOI: https://doi.org/10.1038/s41419-023-05988-6
Autophagy. 2023 Jul 16.

Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.

Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Nobuo N Noda, Tomotake Kanki.

  Mitophagy is a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation. During mitophagy, specific selective autophagy receptors (SARs) mark a portion of mitochondria to recruit the autophagy-related (Atg) machinery and nucleate a phagophore. The phagophore expands and surrounds the mitochondrial cargo, forming an autophagosome. Fission plays a crucial role in separating the targeted portion of mitochondria from the main body to sequester it within the autophagosome. Our recent study, utilizing fission and budding yeasts as model systems, has identified Atg44 as a mitochondrial fission factor that generates mitochondrial fragments suitable for phagophore engulfment. Atg44 resides in the mitochondrial intermembrane space (IMS) and interacts with lipid membranes, with the capacity of mediating membrane fragility and fission. Based on our findings, we propose the term mitofissin to refer to Atg44 and its homologous proteins, which might participate in diverse cellular processes requiring membrane remodeling across various species.

Keywords:  Atg44; autophagy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast

DOI:  https://doi.org/10.1080/15548627.2023.2237343
Front Genet. 2023 ;14 1215083

Mitochondrial depletion syndrome type 3: the Lebanese variant.

Marianne Majdalani, Nadine Yazbeck, Lamis El Harake, Jinane Samaha, Pascale E Karam.

  Introduction: Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene, which encodes for mitochondrial maintenance. This autosomal recessive disorder is frequent in the Middle East and North Africa. Diagnosis is often delayed due to the non-specificity of clinical presentation with cerebro-hepatic deterioration. The only therapeutic option is liver transplantation, although the value of this remains debatable. Methods: We describe the clinical, biochemical, and molecular profiles of Lebanese patients with this rare disorder. We also present a review of all cases from the Middle East and North Africa. Results: All Lebanese patients share a unique mutation, unreported in other populations. Almost half of patients worldwide originate from the Middle East and North Africa, with cases reported from only 7 of the 21 countries in this region. Clinical presentation is heterogeneous, with early-onset neurological and hepatic signs. Liver failure and lactic acidosis are constants. Several variants can be identified in each population; a unique c.235C>T p. (Gln79*) pathogenic variant is found in Lebanese patients. Outcome is poor, with death before 1 year of age. Conclusion: The pathogenic nonsense variant c.235C>T p. (Gln79*) in the deoxyguanosine kinase gene may be considered a founder mutation in Lebanon. Further genotypic delineation of this devastating disorder in populations with high consanguinity rates is needed.

Keywords:  DGUOK; Lebanon; MENA; lactic acidosis; liver transplantation; mitochondrial depletion; mtDNA maintenance defects; neonatal liver failure

DOI:  https://doi.org/10.3389/fgene.2023.1215083
Nat Commun. 2023 07 19. 14(1): 4356

Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.

Luis Rios, Suman Pokhrel, Sin-Jin Li, Gwangbeom Heo, Bereketeab Haileselassie, Daria Mochly-Rosen.

The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.

DOI: https://doi.org/10.1038/s41467-023-40043-0
iScience. 2023 Jul 21. 26(7): 107220

Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation.

Jinsong Wei, Shuai Wang, Haozhe Zhu, Wei Cui, Jianan Gao, Ce Gao, Bo Yu, Bojing Liu, Jun Chen, Jinrong Peng.

  Copper is an essential component in the mitochondrial respiratory chain complex IV (cytochrome c oxidases). However, whether any nucleolar factor(s) is(are) involved in regulating the mitochondrial copper homeostasis remains unclear. The nucleolar localized Def-Capn3 protein degradation pathway cleaves target proteins, including p53, in both zebrafish and human nucleoli. Here, we report that hepatic depletion of mDEF in mice causes an excessive copper accumulation in the mitochondria. We find that mDEF-depleted hepatocytes show an exclusion of CAPN3 from the nucleoli and accumulate p53 and NRF1 proteins in the nucleoli. Furthermore, we find that NRF1 is a CAPN3 substrate. Elevated p53 and NRF1 enhances the expression of Sco2 and Cox genes, respectively, to allow more copper acquirement in the mDefloxp/loxp, Alb:Cre mitochondria. Our findings reveal that the mDEF-CAPN3 pathway serves as a novel mechanism for regulating the mitochondrial copper homeostasis through targeting its substrates p53 and NRF1.

Keywords:  Biological sciences; Cell biology; Hepatology; Molecular biology; Sequence analysis

DOI:  https://doi.org/10.1016/j.isci.2023.107220
Front Physiol. 2023 ;14 1082953

Our current understanding of the toxicity of altered mito-ribosomal fidelity during mitochondrial protein synthesis: What can it tell us about human disease?

Antón Vila-Sanjurjo, Natalia Mallo, John F Atkins, Joanna L Elson, Paul M Smith.

  Altered mito-ribosomal fidelity is an important and insufficiently understood causative agent of mitochondrial dysfunction. Its pathogenic effects are particularly well-known in the case of mitochondrially induced deafness, due to the existence of the, so called, ototoxic variants at positions 847C (m.1494C) and 908A (m.1555A) of 12S mitochondrial (mt-) rRNA. It was shown long ago that the deleterious effects of these variants could remain dormant until an external stimulus triggered their pathogenicity. Yet, the link from the fidelity defect at the mito-ribosomal level to its phenotypic manifestation remained obscure. Recent work with fidelity-impaired mito-ribosomes, carrying error-prone and hyper-accurate mutations in mito-ribosomal proteins, have started to reveal the complexities of the phenotypic manifestation of mito-ribosomal fidelity defects, leading to a new understanding of mtDNA disease. While much needs to be done to arrive to a clear picture of how defects at the level of mito-ribosomal translation eventually result in the complex patterns of disease observed in patients, the current evidence indicates that altered mito-ribosome function, even at very low levels, may become highly pathogenic. The aims of this review are three-fold. First, we compare the molecular details associated with mito-ribosomal fidelity to those of general ribosomal fidelity. Second, we gather information on the cellular and organismal phenotypes associated with defective translational fidelity in order to provide the necessary grounds for an understanding of the phenotypic manifestation of defective mito-ribosomal fidelity. Finally, the results of recent experiments directly tackling mito-ribosomal fidelity are reviewed and future paths of investigation are discussed.

Keywords:  deafness (hearing loss); longevity; mito-ribosome; mitochondrial rRNA mutations; mtDNA; mtDNA diseases; proteostasis; translational fidelity

DOI:  https://doi.org/10.3389/fphys.2023.1082953
Life Sci. 2023 Jul 15. pii: S0024-3205(23)00578-7. [Epub ahead of print]329 121943

The emerging significance of mitochondrial targeted strategies in NAFLD treatment.

Tao Zhang, Yingli Nie, Jiliang Wang.

  Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, ranging from liver steatosis to nonalcoholic steatohepatitis, which ultimately progresses to fibrosis, cirrhosis, and hepatocellular carcinoma. Individuals with NAFLD have a higher risk of developing cardiovascular and extrahepatic cancers. Despite the great progress being made in understanding the pathogenesis and the introduction of new pharmacological targets for NAFLD, no drug or intervention has been accepted for its management. Recent evidence suggests that NAFLD may be a mitochondrial disease, as mitochondrial dysfunction is involved in the pathological processes that lead to NAFLD. In this review, we describe the recent advances in our understanding of the mechanisms associated with mitochondrial dysfunction in NAFLD progression. Moreover, we discuss recent advances in the efficacy of mitochondria-targeted compounds (e.g., Mito-Q, MitoVit-E, MitoTEMPO, SS-31, mitochondrial uncouplers, and mitochondrial pyruvate carrier inhibitors) for treating NAFLD. Furthermore, we present some medications currently being tested in clinical trials for NAFLD treatment, such as exercise, mesenchymal stem cells, bile acids and their analogs, and antidiabetic drugs, with a focus on their efficacy in improving mitochondrial function. Based on this evidence, further investigations into the development of mitochondria-based agents may provide new and promising alternatives for NAFLD management.

Keywords:  Mitochondrial dysfunction; Mitochondrial quality control; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Reactive oxygen species; Therapeutics

DOI:  https://doi.org/10.1016/j.lfs.2023.121943
Child Neurol Open. 2023 Jan-Dec;10:10 2329048X231184183

Broadening the Spectrum of SLC22A5 Phenotype: Primary Carnitine Deficiency Presenting with Focal Myoclonus.

Maymunah Khries, Albert Lim, Dipayan Mitra, Mark Anderson, Jan Bengtsson, Ann Bowron, Elizabeth Harris, Jessica Blickwedel, Karen Wood, Anna P Basu.

  Primary carnitine deficiency (PCD) is caused by pathogenic variants of the SLC22A5 gene, which encodes a transmembrane protein that functions as a high affinity carnitine transporter. Carnitine is essential for the transport of acyl-CoA, produced from fatty acids, into the mitochondria where they are oxidised to produce energy. We present the case history of an 8-year-old boy who presented with fever, lethargy, focal rhythmic (3 Hz) left wrist twitching, and severe encephalopathy. MRI brain showed basal ganglia involvement. Metabolic investigations revealed low serum carnitine; whole genome sequencing confirmed compound heterozygous SLC22A5 mutations. With carnitine replacement, intensive care support, and neurorehabilitation, he made a remarkable recovery, regaining independent breathing, speech, mobility, and hand use. Seizure presentation in PCD is rare and presentation with sustained focal myoclonus has not been previously reported. This case expands the known phenotype of PCD. Prompt carnitine replacement is imperative.

Keywords:  focal myoclonus; genotype phenotype; primary carnitine deficiency

DOI:  https://doi.org/10.1177/2329048X231184183
Nat Metab. 2023 Jul 17.

Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition.

Brenda Morant-Ferrando, Daniel Jimenez-Blasco, Paula Alonso-Batan, Jesús Agulla, Rebeca Lapresa, Dario Garcia-Rodriguez, Sara Yunta-Sanchez, Irene Lopez-Fabuel, Emilio Fernandez, Peter Carmeliet, Angeles Almeida, Marina Garcia-Macia, Juan P Bolaños.

Having direct access to brain vasculature, astrocytes can take up available blood nutrients and metabolize them to fulfil their own energy needs and deliver metabolic intermediates to local synapses1,2. These glial cells should be, therefore, metabolically adaptable to swap different substrates. However, in vitro and in vivo studies consistently show that astrocytes are primarily glycolytic3-7, suggesting glucose is their main metabolic precursor. Notably, transcriptomic data8,9 and in vitro10 studies reveal that mouse astrocytes are capable of mitochondrially oxidizing fatty acids and that they can detoxify excess neuronal-derived fatty acids in disease models11,12. Still, the factual metabolic advantage of fatty acid use by astrocytes and its physiological impact on higher-order cerebral functions remain unknown. Here, we show that knockout of carnitine-palmitoyl transferase-1A (CPT1A)-a key enzyme of mitochondrial fatty acid oxidation-in adult mouse astrocytes causes cognitive impairment. Mechanistically, decreased fatty acid oxidation rewired astrocytic pyruvate metabolism to facilitate electron flux through a super-assembled mitochondrial respiratory chain, resulting in attenuation of reactive oxygen species formation. Thus, astrocytes naturally metabolize fatty acids to preserve the mitochondrial respiratory chain in an energetically inefficient disassembled conformation that secures signalling reactive oxygen species and sustains cognitive performance.

DOI: https://doi.org/10.1038/s42255-023-00835-6
Cell Death Differ. 2023 Jul 17.

Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions.

Paolo Bernardi, Christoph Gerle, Andrew P Halestrap, Elizabeth A Jonas, Jason Karch, Nelli Mnatsakanyan, Evgeny Pavlov, Shey-Shing Sheu, Alexander A Soukas.

The mitochondrial permeability transition (mPT) describes a Ca2+-dependent and cyclophilin D (CypD)-facilitated increase of inner mitochondrial membrane permeability that allows diffusion of molecules up to 1.5 kDa in size. It is mediated by a non-selective channel, the mitochondrial permeability transition pore (mPTP). Sustained mPTP opening causes mitochondrial swelling, which ruptures the outer mitochondrial membrane leading to subsequent apoptotic and necrotic cell death, and is implicated in a range of pathologies. However, transient mPTP opening at various sub-conductance states may contribute several physiological roles such as alterations in mitochondrial bioenergetics and rapid Ca2+ efflux. Since its discovery decades ago, intensive efforts have been made to identify the exact pore-forming structure of the mPT. Both the adenine nucleotide translocase (ANT) and, more recently, the mitochondrial F1FO (F)-ATP synthase dimers, monomers or c-subunit ring alone have been implicated. Here we share the insights of several key investigators with different perspectives who have pioneered mPT research. We critically assess proposed models for the molecular identity of the mPTP and the mechanisms underlying its opposing roles in the life and death of cells. We provide in-depth insights into current controversies, seeking to achieve a degree of consensus that will stimulate future innovative research into the nature and role of the mPTP.

DOI: https://doi.org/10.1038/s41418-023-01187-0
J Vis Exp. 2023 06 30.

Using Live Cell STED Imaging to Visualize Mitochondrial Inner Membrane Ultrastructure in Neuronal Cell Models.

Emery L Ng, Ashley L Reed, Christopher B O'Connell, Nathan N Alder.

Mitochondria play many essential roles in the cell, including energy production, regulation of Ca2+ homeostasis, lipid biosynthesis, and production of reactive oxygen species (ROS). These mitochondria-mediated processes take on specialized roles in neurons, coordinating aerobic metabolism to meet the high energy demands of these cells, modulating Ca2+ signaling, providing lipids for axon growth and regeneration, and tuning ROS production for neuronal development and function. Mitochondrial dysfunction is therefore a central driver in neurodegenerative diseases. Mitochondrial structure and function are inextricably linked. The morphologically complex inner membrane with structural infolds called cristae harbors many molecular systems that perform the signature processes of the mitochondrion. The architectural features of the inner membrane are ultrastructural and therefore, too small to be visualized by traditional diffraction-limited resolved microscopy. Thus, most insights on mitochondrial ultrastructure have come from electron microscopy on fixed samples. However, emerging technologies in super-resolution fluorescence microscopy now provide resolution down to tens of nanometers, allowing visualization of ultrastructural features in live cells. Super-resolution imaging therefore offers an unprecedented ability to directly image fine details of mitochondrial structure, nanoscale protein distributions, and cristae dynamics, providing fundamental new insights that link mitochondria to human health and disease. This protocol presents the use of stimulated emission depletion (STED) super-resolution microscopy to visualize the mitochondrial ultrastructure of live human neuroblastoma cells and primary rat neurons. This procedure is organized into five sections: (1) growth and differentiation of the SH-SY5Y cell line, (2) isolation, plating, and growth of primary rat hippocampal neurons, (3) procedures for staining cells for live STED imaging, (4) procedures for live cell STED experiments using a STED microscope for reference, and (5) guidance for segmentation and image processing using examples to measure and quantify morphological features of the inner membrane.

DOI: https://doi.org/10.3791/65561
Am J Physiol Gastrointest Liver Physiol. 2023 Jul 18.

Medium-chain fatty acid oxidation is independent of L-carnitine in liver and kidney but not in heart and skeletal muscle.

Andrea S Pereyra, Kelsey L McLaughlin, Katherine A Buddo, Jessica M Ellis.

  Medium-chain fatty acid (MCFA) consumption confers a wide range of health benefits that are highly distinct from long-chain fatty acids (LCFA). A major difference between the metabolism of LCFAs compared to MCFAs is that mitochondrial LCFA oxidation depends on the carnitine shuttle, whereas MCFA mitochondrial oxidation is not. Although MCFAs are said to range from 6 to 14 carbons long based on physicochemical properties in vitro, the biological cut-off length of acyl chains that can bypass the carnitine shuttle in different mammalian tissues is unknown. To define the range of acyl chain length that can be oxidized in the mitochondria independent of carnitine, we determined the oxidative metabolism of free fatty acids (FFAs) from 6 to 18 carbons long in the liver, kidney, heart, and skeletal muscle. The liver oxidized FFAs 6 to 14 carbons long, while the kidney oxidized FFAs from 6 to 10 carbons in length. Heart and skeletal muscle were unable to oxidize FFAs of any chain length. These data show that while the liver and kidney can oxidize MCFAs in the free form, the heart and skeletal muscle require carnitine for the oxidative metabolism of MCFAs. Together these data demonstrate that MCFA oxidation independent of carnitine is tissue-specific.

Keywords:  carnitine; liver; medium-chain fatty acids; mitochondrial fatty acid oxidation; skeletal muscle

DOI:  https://doi.org/10.1152/ajpgi.00105.2023
Prog Retin Eye Res. 2023 Jul 15. pii: S1350-9462(23)00044-7. [Epub ahead of print]96 101205

Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens.

Juan Ignacio Jiménez-Loygorri, Rocío Benítez-Fernández, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Beatriz Villarejo-Zori, Raquel Gómez-Sintes, Patricia Boya.

  Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.

Keywords:  Age-related macular degeneration; Autophagy; Diabetic retinopathy; Glaucoma; Metabolism; Mitochondria; Mitophagy; Retinal development; Retinal homeostasis; Retinitis pigmentosa

DOI:  https://doi.org/10.1016/j.preteyeres.2023.101205
J Biol Chem. 2023 Jul 13. pii: S0021-9258(23)02074-4. [Epub ahead of print] 105046

FDX1 regulates cellular protein lipoylation through direct binding to LIAS.

Margaret B Dreishpoon, Nolan R Bick, Boryana Petrova, Douglas M Warui, Alison Cameron, Squire J Booker, Naama Kanarek, Todd R Golub, Peter Tsvetkov.

Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of ferredoxins as electron donors enables them to participate in many metabolic processes including steroid, heme, vitamin D and Fe-S cluster biosynthesis in different organisms. However, the unique natural function(s) of each of the two human ferredoxins (FDX1 and FDX2) are still poorly characterized. We recently reported that FDX1 is both a crucial regulator of copper ionophore induced cell death and serves as an upstream regulator of cellular protein lipoylation, a mitochondrial lipid-based post translational modification naturally occurring on four mitochondrial enzymes that are crucial for TCA cycle function. Here we show that FDX1 directly regulates protein lipoylation by binding the lipoyl synthase (LIAS) enzyme promoting its functional binding to the lipoyl carrier protein GCSH and not through indirect regulation of cellular Fe-S cluster biosynthesis. Metabolite profiling revealed that the predominant cellular metabolic outcome of FDX1 loss-of-function is manifested through the regulation of the four lipoylation-dependent enzymes ultimately resulting in loss of cellular respiration and sensitivity to mild glucose starvation. Transcriptional profiling established that FDX1 loss-of-function results in the induction of both compensatory metabolism related genes and the integrated stress response, consistent with our findings that FDX1 loss-of-function is conditionally lethal. Together, our findings establish that FDX1 directly engages with LIAS, promoting its role in cellular protein lipoylation, a process essential in maintaining cell viability under low glucose conditions.

DOI: https://doi.org/10.1016/j.jbc.2023.105046
Nat Commun. 2023 07 19. 14(1): 4360

Nuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism.

Shubhi Srivastava, Priyanka Gajwani, Jordan Jousma, Hiroe Miyamoto, Youjeong Kwon, Arundhati Jana, Peter T Toth, Gege Yan, Sang-Ging Ong, Jalees Rehman.

Chemotherapy-induced cardiac damage remains a leading cause of death amongst cancer survivors. Anthracycline-induced cardiotoxicity is mediated by severe mitochondrial injury, but little is known about the mechanisms by which cardiomyocytes adaptively respond to the injury. We observed the translocation of selected mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases to the nucleus as an adaptive stress response to anthracycline-cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes and in vivo. The expression of nuclear-targeted mitochondrial dehydrogenases shifts the nuclear metabolic milieu to maintain their function both in vitro and in vivo. This protective effect is mediated by two parallel pathways: metabolite-induced chromatin accessibility and AMP-kinase (AMPK) signaling. The extent of chemotherapy-induced cardiac damage thus reflects a balance between mitochondrial injury and the protective response initiated by the nuclear pool of mitochondrial dehydrogenases. Our study identifies nuclear translocation of mitochondrial dehydrogenases as an endogenous adaptive mechanism that can be leveraged to attenuate cardiomyocyte injury.

DOI: https://doi.org/10.1038/s41467-023-40084-5
Eur J Hum Genet. 2023 Jul 19.

A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.

Dario Ronchi, Manuela Garbellini, Francesca Magri, Francesca Menni, Megi Meneri, Maria Francesca Bedeschi, Robertino Dilena, Valeria Cecchetti, Irene Picciolli, Francesca Furlan, Valentina Polimeni, Sabrina Salani, Laura Pezzoli, Francesco Fortunato, Matteo Bellini, Daniela Piga, Michela Ripolone, Simona Zanotti, Laura Napoli, Patrizia Ciscato, Monica Sciacco, Giovanna Mangili, Fabio Mosca, Stefania Corti, Maria Iascone, Giacomo Pietro Comi.

Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. Serum lactate was consistently increased. Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18. Patient's muscle biopsy revealed severe and diffuse COX deficiency and striking mitochondrial abnormalities. Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly. The biochemical defect was partially rescued by delivery of wild-type COX18 cDNA into patient's myoblasts. Our study identifies a novel defect of COX assembly and expands the number of nuclear genes involved in a mitochondrial disorder due to isolated COX deficiency.

DOI: https://doi.org/10.1038/s41431-023-01433-6
Nat Cell Biol. 2023 Jul 19.

Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP).

HuBMAP Consortium

The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research.

DOI: https://doi.org/10.1038/s41556-023-01194-w
Sci Adv. 2023 Jul 21. 9(29): eadi4862

What is really known about the effects of nicotinamide riboside supplementation in humans.

Mads V Damgaard, Jonas T Treebak.

Nicotinamide riboside is a precursor to the important cofactor nicotinamide adenine dinucleotide and has elicited metabolic benefits in multiple preclinical studies. In 2016, the first clinical trial of nicotinamide riboside was conducted to test the safety and efficacy of human supplementation. Many trials have since been conducted aiming to delineate benefits to metabolic health and severe diseases in humans. This review endeavors to summarize and critically assess the 25 currently published research articles on human nicotinamide riboside supplementation to identify any poorly founded claims and assist the field in elucidating the actual future potential for nicotinamide riboside. Collectively, oral nicotinamide riboside supplementation has displayed few clinically relevant effects, and there is an unfortunate tendency in the literature to exaggerate the importance and robustness of reported effects. Even so, nicotinamide riboside may play a role in the reduction of inflammatory states and has shown some potential in the treatment of diverse severe diseases.

DOI: https://doi.org/10.1126/sciadv.adi4862
Exp Neurol. 2023 Jul 14. pii: S0014-4886(23)00164-4. [Epub ahead of print] 114479

Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery.

Mariajose Metcalfe, Brian T David, Brett C Langley, Caitlin E Hill.

  Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days, and weeks following injury, leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD+-dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD+ depletion propagates tissue damage. Augmenting NAD+ by exogenous application of NAD+, its synthesizing enzymes, or its cellular precursors mitigates tissue damage. Nicotinamide riboside (NR) is considered to be one of the most promising NAD+ precursors for clinical application due to its ability to safely and effectively boost cellular NAD+ synthesis in rats and humans. Moreover, various preclinical studies have demonstrated that NR can provide tissue protection. Despite these promising findings, little is known about the potential benefits of NR in the context of SCI. In the current study, we tested whether NR administration could effectively increase NAD+ levels in the injured spinal cord and whether this augmentation of NAD+ would promote spinal cord tissue protection and ultimately lead to improvements in locomotor function. Our findings indicate that administering NR (500 mg/kg) via intraperitoneal route, four days before and two weeks after a mid-thoracic contusion-SCI injury, effectively doubles NAD+ levels in the spinal cord of Long-Evans rats. Moreover, NR administration plays a protective role in preserving spinal cord tissue post-injury, particularly in neurons and axons, as evident from the observed gray and white matter sparing. Additionally, it enhances motor function, as evaluated through the BBB subscore and missteps on the horizontal ladderwalk. Collectively, these findings demonstrate that administering NR, a precursor of NAD+ increases NAD+ within the injured spinal cord and effectively mitigates the tissue damage and functional decline that occurs following SCI.

Keywords:  Nicotinamide adenine dinucleotide; Nicotinamide riboside; Spinal cord injury

DOI:  https://doi.org/10.1016/j.expneurol.2023.114479
Nutr Rev. 2023 Jul 20. pii: nuad084. [Epub ahead of print]

Nutritional approaches targeting mitochondria for the prevention of sarcopenia.

Jeong-Hoon Hahm, Farida S Nirmala, Tae Youl Ha, Jiyun Ahn.

  A decline in function and loss of mass, a condition known as sarcopenia, is observed in the skeletal muscles with aging. Sarcopenia has a negative effect on the quality of life of elderly. Individuals with sarcopenia are at particular risk for adverse outcomes, such as reduced mobility, fall-related injuries, and type 2 diabetes mellitus. Although the pathogenesis of sarcopenia is multifaceted, mitochondrial dysfunction is regarded as a major contributor for muscle aging. Hence, the development of preventive and therapeutic strategies to improve mitochondrial function during aging is imperative for sarcopenia treatment. However, effective and specific drugs that can be used for the treatment are not yet approved. Instead studies on the relationship between food intake and muscle aging have suggested that nutritional intake or dietary control could be an alternative approach for the amelioration of muscle aging. This narrative review approaches various nutritional components and diets as a treatment for sarcopenia by modulating mitochondrial homeostasis and improving mitochondria. Age-related changes in mitochondrial function and the molecular mechanisms that help improve mitochondrial homeostasis are discussed, and the nutritional components and diet that modulate these molecular mechanisms are addressed.

Keywords:  diet; mitochondria; muscle aging; nutrition; sarcopenia

DOI:  https://doi.org/10.1093/nutrit/nuad084
Biol Res. 2023 Jul 20. 56(1): 42

Investigating the dark-side of the genome: a barrier to human disease variant discovery?

Niamh M Ryan, Aiden Corvin.

  The human genome contains regions that cannot be adequately assembled or aligned using next generation short-read sequencing technologies. More than 2500 genes are known contain such 'dark' regions. In this study, we investigate the negative consequences of dark regions on gene discovery across a range of disease and study types, showing that dark regions are likely preventing researchers from identifying genetic variants relevant to human disease.

Keywords:  Dark regions; Gene-disease associations; Short-read sequencing

DOI:  https://doi.org/10.1186/s40659-023-00455-0
bioRxiv. 2023 Jul 04. pii: 2023.07.04.547719. [Epub ahead of print]

Design, Synthesis, and Biological Evaluation of Novel Mitochondria-targeting Exosomes.

Xin Yan, Xinqian Chen, Zhiying Shan, Lanrong Bi.

Mitochondrial dysfunction is implicated in both brain tumors and neurodegenerative diseases, leading to various cellular abnormalities that can promote tumor growth and resistance to thera-pies, as well as impaired energy production and compromised neuronal function. Developing targeted therapies aimed at restoring mitochondrial function and improving overall cellular health could potentially be a promising approach to treating these conditions. Brain-derived exosomes (BR-EVs) have emerged as potential drug delivery vessels for neurological conditions. Herein, we report a new method for creating mitochondria-targeting exosomes and test its application in vitro and in vivo.

DOI: https://doi.org/10.1101/2023.07.04.547719
Bioinformatics. 2023 Jul 17. pii: btad440. [Epub ahead of print]

RDBridge: a knowledge graph of rare diseases based on large-scale text mining.

Huadong Xing, Dachuan Zhang, Pengli Cai, Rui Zhang, Qian-Nan Hu.

MOTIVATION: Despite low prevalence, rare diseases affect 300 million people worldwide. Research on pathogenesis and drug development lags due to limited commercial potential, insufficient epidemiological data, and a dearth of publications. The unique characteristics of rare diseases, including limited annotated data, intricate processes for extracting pertinent entity relationships, and difficulties in standardizing data, represent challenges for text mining.
RESULTS: We developed a rare disease data acquisition framework using text mining and knowledge graphs and constructed the most comprehensive rare disease knowledge graph to date, Rare Disease Bridge (RDBridge). RDBridge offers search functions for genes, potential drugs, pathways, literature, and medical imaging data that will support mechanistic research, drug development, diagnosis, and treatment for rare diseases.
AVAILABILITY AND IMPLEMENTATION: RDBridge is freely available at http://rdb.lifesynther.com/.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btad440
Nature. 2023 Jul;619(7970): 465

Quantum sensors: detect heart disease sooner.

Bettina Heidecker.



Keywords:  Diseases; Quantum physics; Technology

DOI:  https://doi.org/10.1038/d41586-023-02247-8
medRxiv. 2023 Jul 06. pii: 2023.07.05.23292247. [Epub ahead of print]

Structure-based network analysis predicts mutations associated with inherited retinal disease.

Blake M Hauser, Yuyang Luo, Anusha Nathan, Gaurav D Gaiha, Demetrios Vavvas, Jason Comander, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Elizabeth J Rossin.

With continued advances in gene sequencing technologies comes the need to develop better tools to understand which mutations cause disease. Here we validate structure-based network analysis (SBNA) 1, 2 in well-studied human proteins and report results of using SBNA to identify critical amino acids that may cause retinal disease if subject to missense mutation. We computed SBNA scores for genes with high-quality structural data, starting with validating the method using 4 well-studied human disease-associated proteins. We then analyzed 47 inherited retinal disease (IRD) genes. We compared SBNA scores to phenotype data from the ClinVar database and found a significant difference between benign and pathogenic mutations with respect to network score. Finally, we applied this approach to 65 patients at Massachusetts Eye and Ear (MEE) who were diagnosed with IRD but for whom no genetic cause was found. Multivariable logistic regression models built using SBNA scores for IRD-associated genes successfully predicted pathogenicity of novel mutations, allowing us to identify likely causative disease variants in 37 patients with IRD from our clinic. In conclusion, SBNA can be meaningfully applied to human proteins and may help predict mutations causative of IRD.

DOI: https://doi.org/10.1101/2023.07.05.23292247
Nat Biotechnol. 2023 Jul 17.

A way forward for diagnosis of patients with extremely rare genetic mutations.

Stanley T Crooke, Olivia S Kim-McManus, Kelley Dalby.

DOI: https://doi.org/10.1038/s41587-023-01879-5
Mol Neurodegener. 2023 Jul 20. 18(1): 49

Axonal energy metabolism, and the effects in aging and neurodegenerative diseases.

Sen Yang, Jung Hyun Park, Hui-Chen Lu.

  Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons. Axons, key components of the connectome, have high metabolic needs to support neurotransmission and other essential activities. Long-range axons are particularly vulnerable to injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy is often an early sign of neurodegeneration. Recent studies ascribe axonal maintenance failures to local bioenergetic dysregulation. With this review, we aim to stimulate research in exploring metabolically oriented neuroprotection strategies to enhance or normalize bioenergetics in NDA models. Here we start by summarizing evidence from human patients and animal models to reveal the correlation between glucose hypometabolism and connectomic disintegration upon aging/NDAs. To encourage mechanistic investigations on how axonal bioenergetic dysregulation occurs during aging/NDAs, we first review the current literature on axonal bioenergetics in distinct axonal subdomains: axon initial segments, myelinated axonal segments, and axonal arbors harboring pre-synaptic boutons. In each subdomain, we focus on the organization, activity-dependent regulation of the bioenergetic system, and external glial support. Second, we review the mechanisms regulating axonal nicotinamide adenine dinucleotide (NAD+) homeostasis, an essential molecule for energy metabolism processes, including NAD+ biosynthetic, recycling, and consuming pathways. Third, we highlight the innate metabolic vulnerability of the brain connectome and discuss its perturbation during aging and NDAs. As axonal bioenergetic deficits are developing into NDAs, especially in asymptomatic phase, they are likely exaggerated further by impaired NAD+ homeostasis, the high energetic cost of neural network hyperactivity, and glial pathology. Future research in interrogating the causal relationship between metabolic vulnerability, axonopathy, amyloid/tau pathology, and cognitive decline will provide fundamental knowledge for developing therapeutic interventions.

Keywords:  Aging; Axonal bioenergetics; Axonopathy; Energy metabolism; Glucose; Glycolysis; Mitochondria; NAD; Neurodegeneration; Neuroprotection

DOI:  https://doi.org/10.1186/s13024-023-00634-3
J Genet. 2023 ;pii: 34. [Epub ahead of print]102

Detecting disease association with rare variants using weighted entropy.

Yu-Mei Li, Yang Xiang.

The rapid development of sequencing technology and simultaneously the availability of large quantities of sequence data provide an unprecedented opportunity for researchers to conduct studies to detect rare variants associated with the disease. However, none of the current existing statistical methods has uniform power in all scenarios because they are more or less affected by nonfunctional variants and variants with opposite effects. Here, we present a robust approach to identify rare variants using weighted entropy theory. Here, this approach takes the proportion of the minor allele among all k variants as its probability distribution, which reduces the noise incurred by noncausal variants, and uses a weight to strike a balance between deleterious rare variants and protective rare variants, which makes our method impacted less by variants with opposite effect. Through simulation studies, we investigate the performance of our method for rare variant association analyses as well as for common variant association analyses and compared it with Burden test and the SKAT. Simulation studies show that the proposed method is valid and affected slightly by noncausal variants and opposite effect variants with high and stable power for various parameters set.
Neurology. 2023 Jul 17. pii: 10.1212/WNL.0000000000207649. [Epub ahead of print]

Child Neurology: Progressive Cerebellar Atrophy and Retinal Dystrophy - Clues to an Ultra-Rare ACO2-Related Neurometabolic Diagnosis.

Noor Lail, Ashutosh K Pandey, Sundararajan Venkatesh, Roberto D Noland, Gabriel Swanson, Debkumar Pain, Helen M Branson, Carolyn K Suzuki, Grace Yoon.

Pathogenic bi-allelic variants in ACO2, which encodes the enzyme mitochondrial aconitase, are associated with the very rare diagnosis of ACO2-related Infantile Cerebellar Retinal Degeneration (OMIM 614559). We describe the diagnostic odyssey of a 4-year-old female patient with profound global developmental delays, microcephaly, severe hypotonia, retinal dystrophy, seizures, and progressive cerebellar atrophy. Whole exome sequencing (WES) revealed two variants in ACO2; c.2105_2106delAG (p.Gln702ArgfsX9), a likely pathogenic variant, and c.988C>T (p.Pro330Ser) which was classified as a variant of uncertain significance (VUS). While the VUS was confirmed to be maternally inherited, the phase of the other variant could not be confirmed due to lack of a paternal sample. Functional biochemical studies were performed on a research basis to clarify the interpretation of the VUS, which enabled clinical confirmation of the diagnosis of ACO2-related Infantile Cerebellar Retinal Degeneration for our patient.

DOI: https://doi.org/10.1212/WNL.0000000000207649
medRxiv. 2023 Jul 03. pii: 2023.06.29.23291992. [Epub ahead of print]

Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.

Frederik H Lassen, Samvida S Venkatesh, Nikolas Baya, Wei Zhou, Alex Bloemendal, Benjamin M Neale, Benedikt M Kessler, Nicola Whiffin, Cecilia M Lindgren, Duncan S Palmer.

Exome-sequencing association studies have successfully linked rare protein-coding variation to risk of thousands of diseases. However, the relationship between rare deleterious compound heterozygous (CH) variation and their phenotypic impact has not been fully investigated. Here, we leverage advances in statistical phasing to accurately phase rare variants (MAF ∼ 0.001%) in exome sequencing data from 175,587 UK Biobank (UKBB) participants, which we then systematically annotate to identify putatively deleterious CH coding variation. We show that 6.5% of individuals carry such damaging variants in the CH state, with 90% of variants occurring at MAF < 0.34%. Using a logistic mixed model framework, systematically accounting for relatedness, polygenic risk, nearby common variants, and rare variant burden, we investigate recessive effects in common complex diseases. We find six exome-wide significant (𝑃 < 1.68 × 10 -7 ) and 17 nominally significant (𝑃 < 5.25 × 10 -5 ) gene-trait associations. Among these, only four would have been identified without accounting for CH variation in the gene. We further incorporate age-at-diagnosis information from primary care electronic health records, to show that genetic phase influences lifetime risk of disease across 20 gene-trait combinations (FDR < 5%). Using a permutation approach, we find evidence for genetic phase contributing to disease susceptibility for a collection of gene-trait pairs, including FLG -asthma (𝑃 = 0.00205) and USH2A -visual impairment (𝑃 = 0.0084). Taken together, we demonstrate the utility of phasing large-scale genetic sequencing cohorts for robust identification of the phenome-wide consequences of compound heterozygosity.

DOI: https://doi.org/10.1101/2023.06.29.23291992