bims-mitdis 2023-11-05 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2023–11–05
33 papers selected by
Catalina Vasilescu, Helmholz Munich

Mitochondria makeover: unlocking the path to healthy longevity.
Mitochondrial complexome and import network.
A human mitofusin 2 mutation can cause mitophagic cardiomyopathy.
Mitochondrial regulation in stem cells.
TBK1 is ubiquitinated by TRIM5α to assemble mitophagy machinery.
Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.
Autoregulatory control of mitochondrial glutathione homeostasis.
Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers.
Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.
Influence of aging, mitochondrial dysfunction, and inflammation on Parkinson's disease.
Genome-wide association study identifies APOE and ZMIZ1 variants as mitophagy modifiers in Lewy body disease.
New roles of LPGAT1: From mitochondrial import of phosphatidylglycerol to MEGDEL disease.
Mitochondrial transport in neurons and evidence for its involvement in acute neurological disorders.
Sexual dimorphism of osteoclast reliance on mitochondrial oxidation of energy substrates in the mouse.
Integrated omics analyses clarifies ATRX copy number variant of uncertain significance.
DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.
Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan.
ATP-Bound State of the Uncoupling Protein 1 (UCP1) from Molecular Simulations.
Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes.
Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.
Advances in the discovery and analyses of human tandem repeats.
LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.
The Role of Mitokines in Diabetic Nephropathy.
Two functionally different mitochondrial phosphate carriers support Drosophila melanogaster OXPHOS throughout distinct developmental stages.
Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis.
UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.
The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.
Real-time resolution studies of the regulation of pyruvate-dependent lactate metabolism by hexokinases in single cells.
Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.
NMR-Based Mitochondria Metabolomic Profiling: A New Approach To Reveal Cancer-Associated Alterations.
OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records.
Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.
The regulatory role of adipocyte mitochondrial homeostasis in metabolism-related diseases.

Expert Opin Ther Targets. 2023 Oct 30. 1-4

Mitochondria makeover: unlocking the path to healthy longevity.

Andrés Caicedo, Keshav K Singh.



Keywords:  Aging; Extracellular Mitochondria; Hallmarks of Aging; Health; Healthy Longevity; Induced Pluripotent Stem Cells (iPSCs); Longevity; Mitochondria; Mitochondrial DNA (mtDNA); Mitochondrial Transfer; Mitochondrial Transplant; Rejuvenation; Senescent Cells; Telomeres

DOI:  https://doi.org/10.1080/14728222.2023.2277240
Trends Cell Biol. 2023 Oct 30. pii: S0962-8924(23)00208-8. [Epub ahead of print]

Mitochondrial complexome and import network.

Fabian den Brave, Uwe Schulte, Bernd Fakler, Nikolaus Pfanner, Thomas Becker.

  Mitochondria perform crucial functions in cellular metabolism, protein and lipid biogenesis, quality control, and signaling. The systematic analysis of protein complexes and interaction networks provided exciting insights into the structural and functional organization of mitochondria. Most mitochondrial proteins do not act as independent units, but are interconnected by stable or dynamic protein-protein interactions. Protein translocases are responsible for importing precursor proteins into mitochondria and form central elements of several protein interaction networks. These networks include molecular chaperones and quality control factors, metabolite channels and respiratory chain complexes, and membrane and organellar contact sites. Protein translocases link the distinct networks into an overarching network, the mitochondrial import network (MitimNet), to coordinate biogenesis, membrane organization and function of mitochondria.

Keywords:  cell organelles; energetics; metabolism; mitochondria; morphology; protein assembly; protein networks; protein sorting

DOI:  https://doi.org/10.1016/j.tcb.2023.10.004
Elife. 2023 Nov 01. pii: e84235. [Epub ahead of print]12

A human mitofusin 2 mutation can cause mitophagic cardiomyopathy.

Antonietta Franco, Jiajia Li, Daniel P Kelly, Ray E Hershberger, Ali J Marian, Renate M Lewis, Moshi Song, Xiawei Dang, Alina D Schmidt, Mary E Mathyer, John R Edwards, Cristina de Guzman Strong, Gerald W Dorn.

  Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy.

Keywords:  cardiomyopathy; developmental biology; heart; mitochondria; mitofusins; mouse

DOI:  https://doi.org/10.7554/eLife.84235
Trends Cell Biol. 2023 Oct 31. pii: S0962-8924(23)00207-6. [Epub ahead of print]

Mitochondrial regulation in stem cells.

Yifei Wang, Marine Barthez, Danica Chen.

  Stem cells persist throughout the lifespan to repair and regenerate tissues due to their unique ability to self-renew and differentiate. Here we reflect on the recent discoveries in stem cells that highlight a mitochondrial metabolic checkpoint at the restriction point of the stem cell cycle. Mitochondrial activation supports stem cell proliferation and differentiation by providing energy supply and metabolites as signaling molecules. Concomitant mitochondrial stress can lead to loss of stem cell self-renewal and requires the surveillance of various mitochondrial quality control mechanisms. During aging, a mitochondrial protective program mediated by several sirtuins becomes dysregulated and can be targeted to reverse stem cell aging and tissue degeneration, giving hope for targeting the mitochondrial metabolic checkpoint for treating tissue degenerative diseases.

Keywords:  NAD; NLRP3; SIRT2; SIRT3; SIRT7; aging

DOI:  https://doi.org/10.1016/j.tcb.2023.10.003
bioRxiv. 2023 Oct 20. pii: 2023.10.19.563195. [Epub ahead of print]

TBK1 is ubiquitinated by TRIM5α to assemble mitophagy machinery.

Bhaskar Saha, Hallvard Olsvik, Geneva L Williams, Seeun Oh, Gry Evjen, Eva Sjøttem, Michael A Mandell.

Ubiquitination of mitochondrial proteins provides a basis for the downstream recruitment of mitophagy machinery, yet whether ubiquitination of the machinery itself contributes to mitophagy is unknown. Here, we show that K63-linked polyubiquitination of the key mitophagy regulator TBK1 is essential for its mitophagy functions. This modification is catalyzed by the ubiquitin ligase TRIM5α. Mitochondrial damage triggers TRIM5α's auto-ubiquitination and its interaction with ubiquitin-binding autophagy adaptors including NDP52, optineurin, and NBR1. Autophagy adaptors, along with TRIM27, enable TRIM5α to engage with TBK1. TRIM5α with intact ubiquitination function is required for the proper accumulation of active TBK1 on damaged mitochondria in Parkin-dependent and Parkin-independent mitophagy pathways. Additionally, we show that TRIM5α can directly recruit autophagy initiation machinery to damaged mitochondria. Our data support a model in which TRIM5α provides a self-amplifying, mitochondria-localized, ubiquitin-based, assembly platform for TBK1 and mitophagy adaptors that is ultimately required to recruit the core autophagy machinery.

DOI: https://doi.org/10.1101/2023.10.19.563195
J Cell Biol. 2023 Dec 04. pii: e202305032. [Epub ahead of print]222(12):

Super-resolution microscopy: Insights into mitochondria-lysosome crosstalk in health and disease.

Eric D Leisten, Abby C Woods, Yvette C Wong.

Live super-resolution microscopy has allowed for new insights into recently identified mitochondria-lysosome contact sites, which mediate crosstalk between mitochondria and lysosomes, including co-regulation of Rab7 GTP hydrolysis and Drp1 GTP hydrolysis. Here, we highlight recent findings and future perspectives on this dynamic pathway and its roles in health and disease.

DOI: https://doi.org/10.1083/jcb.202305032
Science. 2023 Nov 02. eadf4154

Autoregulatory control of mitochondrial glutathione homeostasis.

Yuyang Liu, Shanshan Liu, Anju Tomar, Frederick S Yen, Gokhan Unlu, Nathalie Ropek, Ross A Weber, Ying Wang, Artem Khan, Mark Gad, Junhui Peng, Erdem Terzi, Hanan Alwaseem, Alexandra E Pagano, Søren Heissel, Henrik Molina, Benjamin Allwein, Timothy C Kenny, Richard L Possemato, Li Zhao, Richard K Hite, Ekaterina V Vinogradova, Sheref S Mansy, Kıvanç Birsoy.

Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. We focused on glutathione (GSH), a critical redox metabolite in mitochondria and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by a mitochondrial protease, AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analysis identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 to be essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.

DOI: https://doi.org/10.1126/science.adf4154
Mol Genet Metab. 2023 Oct 20. pii: S1096-7192(23)00340-2. [Epub ahead of print] 107710

Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers.

Parith Wongkittichote, Cassandra Pantano, Emily Bogush, Cesar Augusto P Alves, Xinying Hong, Miao He, Matthew M Demczko, Rebecca D Ganetzky, Amy Goldstein.

  Iron‑sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries. IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.

Keywords:  IBA57; Iron‑sulfur clusters; Lysine metabolism; Mitochondrial disorder; Rhabdomyolysis

DOI:  https://doi.org/10.1016/j.ymgme.2023.107710
Am J Med Genet A. 2023 Nov 03.

Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.

Care4Rare Canada Consortium

  Our understanding of genetic and phenotypic heterogeneity associated with the clinical spectrum of rare diseases continues to expand. Thorough phenotypic descriptions and model organism functional studies are valuable tools in dissecting the biology of the disease process. Kinesin genes are well known to be associated with specific disease phenotypes and a subset of kinesin genes, including KIF21A, have been associated with more than one disease. Here we report two patients with KIF21A variants identified by exome sequencing; one with biallelic variants, supporting a novel KIF21A related syndrome with recessive inheritance and the second report of this condition, and another with a heterozygous de novo variant allele representing a phenotypic expansion of the condition described to date. We provide detailed phenotypic information on both families, including a novel neuropathology finding of neuroaxonal dystrophy associated with biallelic variants in KIF21A. Additionally, we studied the dominant variant in Saccharomyces cerevisiae to assess variant pathogenicity and found that this variant appears to impair protein function. KIF21A associated disease has mounting evidence for phenotypic heterogeneity; further patients and study of an allelic series are required to define the phenotypic spectrum and further explore the molecular etiology for each of these conditions.

Keywords:  KIF21A; fetal arthrogryposis; model organisms; neuroaxonal dystrophy; phenotypic heterogeneity; yeast model

DOI:  https://doi.org/10.1002/ajmg.a.63455
Neural Regen Res. 2024 Jun 01. 19(6): 1197-1198

Influence of aging, mitochondrial dysfunction, and inflammation on Parkinson's disease.

Davide Cossu, Nobutaka Hattori.

DOI: https://doi.org/10.4103/1673-5374.385873
medRxiv. 2023 Oct 16. pii: 2023.10.16.23297100. [Epub ahead of print]

Genome-wide association study identifies APOE and ZMIZ1 variants as mitophagy modifiers in Lewy body disease.

Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Alexandra I Soto-Beasley, Jens O Watzlawik, Jing Zhao, Rebecca R Valentino, Patrick W Johnson, Launia J White, Zachary S Quicksall, Joseph S Reddy, Jose Bras, Rita Guerreiro, Na Zhao, Guojun Bu, Dennis W Dickson, Owen A Ross, Wolfdieter Springer.

The PINK1-PRKN pathway mediates a critical quality control to maintain mitochondrial health and function. Together the kinase-ligase pair identifies and decorate damaged mitochondria with phosphorylated ubiquitin (p-S65-Ub). This selective label serves as the mitophagy tag and facilitates their degradation via autophagy-lysosome system. While complete loss of PINK1 or PRKN function causes early-onset Parkinson disease, much broader mitophagy impairments are emerging across neurodegenerative disorders. We previously found age- and disease-dependent accumulation of p-S65-Ub signal in the hippocampus of autopsy brains with Lewy body disease (LBD). However, the contribution of genetic variation to mitochondrial damage and p-S65-Ub levels remains unknown in LBD cases. To identify novel regulators of PINK1-PRKN mitophagy in LBD, we performed an unbiased genome-wide association study of hippocampal p-S65-Ub level with 1,012 autopsy confirmed LBD samples. Using an established, mostly automated workflow, hippocampal sections were immunostained for p-S65-Ub, scanned, and quantified with unbiased algorithms. Functional validation of the significant hit was performed in animal model and human induced pluripotent stem cells (hiPSCs). We identified a strong association with p-S65-Ub for APOE4 (rs429358; β : 0.50, 95% CI: 0.41 to 0.69; p =8.67x10 -25 ) and a genome-wide significant association for ZMIZ1 (rs6480922; β : -0.33, 95% CI: -0.45 to -0.22; p =1.42x10 -8 ). The increased p-S65-Ub levels in APOE4 -carrier may be mediated by both co-pathology-dependent and -independent mechanisms, which was confirmed in Apoe-targeted replacement mice and hiPSC-derived astrocytes. Intriguingly, ZMIZ1 rs6480922 also significantly associated with increased brain weight and reduced neuropathological burden indicating a potential role as a resilience factor. Our findings nominate novel mitophagy regulators in LBD brain ( ZMIZ1 locus) and highlight a strong association of APOE4 with mitophagy alteration. With APOE4 being the strongest known risk factor for clinical Alzheimer's disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.

DOI: https://doi.org/10.1101/2023.10.16.23297100
Cell Rep. 2023 Nov 01. pii: S2211-1247(23)01388-8. [Epub ahead of print]42(11): 113376

New roles of LPGAT1: From mitochondrial import of phosphatidylglycerol to MEGDEL disease.

Vera Filipa Monteiro-Cardoso, Francesca Giordano.

Dysregulation of mitochondrial lipidome is associated with several human pathologies. Sun et al.1 show that LPGAT1 cooperates with TIMM14 to regulate phosphatidylglycerol transport from the endoplasmic reticulum to the mitochondria, and uncover the involvement of LPGAT1 deficiency in MEGDEL syndrome.

DOI: https://doi.org/10.1016/j.celrep.2023.113376
Front Neurosci. 2023 ;17 1268883

Mitochondrial transport in neurons and evidence for its involvement in acute neurological disorders.

Dengfeng Lu, Yun Feng, Guangjie Liu, Yayi Yang, Yubo Ren, Zhouqing Chen, Xiaoou Sun, Yixiang Guan, Zhong Wang.

  Ensuring mitochondrial quality is essential for maintaining neuronal homeostasis, and mitochondrial transport plays a vital role in mitochondrial quality control. In this review, we first provide an overview of neuronal mitochondrial transport, followed by a detailed description of the various motors and adaptors associated with the anterograde and retrograde transport of mitochondria. Subsequently, we review the modest evidence involving mitochondrial transport mechanisms that has surfaced in acute neurological disorders, including traumatic brain injury, spinal cord injury, spontaneous intracerebral hemorrhage, and ischemic stroke. An in-depth study of this area will help deepen our understanding of the mechanisms underlying the development of various acute neurological disorders and ultimately improve therapeutic options.

Keywords:  TRAK; acute neurological disorders; dynein; kinesin; miro; myosin

DOI:  https://doi.org/10.3389/fnins.2023.1268883
JCI Insight. 2023 Nov 02. pii: e174293. [Epub ahead of print]

Sexual dimorphism of osteoclast reliance on mitochondrial oxidation of energy substrates in the mouse.

Chao Song, Arianna Valeri, Fangfang Song, Xing Ji, Xueyang Liao, Tyler Marmo, Rebecca A Seeley, Jared Rutter, Fanxin Long.

  Osteoclasts specialize in bone resorption and are critical for bone remodeling. Previous studies have shown that osteoclasts possess abundant mitochondria and derive most energy through oxidative phosphorylation (OXPHOS). However, the energy substrates fueling OXPHOS in osteoclasts remain to be fully defined. Here, we showed that osteoclast differentiation was coupled with increased oxidation of glucose, glutamine and oleate. Transcriptomic analyses with RNA sequencing revealed marked upregulation of genes participating in OXPHOS and mitochondrial fatty acids oxidation, during osteoclast differentiation. Increased mitochondrial oxidation of long-chain fatty acids was required for osteoclast differentiation in vitro. However, blocking fatty acid oxidation in vivo, by deletion of Cpt1a in osteoclast progenitors, impaired osteoclast formation only in the female mice. The Cpt1a-deficient females were further protected from osteoclast activation by a high fat diet. The males, on the contrary, exhibited normal bone resorption despite Cpt1a deletion, regardless of the dietary fat content. Moreover, concurrent deletion of Mpc1 and Cpt1a, blocking mitochondrial oxidation of both glucose and fatty acids in the osteoclast lineage, failed to impede bone resorption in the males. The study therefore uncovers a female-specific dependence on mitochondrial oxidation of fatty acids and glucose in osteoclasts in vivo.

Keywords:  Bioenergetics; Bone Biology; Osteoclast/osteoblast biology

DOI:  https://doi.org/10.1172/jci.insight.174293
J Hum Genet. 2023 Oct 31.

Integrated omics analyses clarifies ATRX copy number variant of uncertain significance.

Care4Rare Canada Consortium

Partial duplications of genes can be challenging to detect and interpret and, therefore, likely represent an underreported cause of human disease. X-linked dominant variants in ATRX are associated with Alpha-thalassemia/impaired intellectual development syndrome, X-linked (ATR-X syndrome), a clinically heterogeneous disease generally presenting with intellectual disability, hypotonia, characteristic facies, genital anomalies, and alpha-thalassemia. We describe an affected male with a de novo hemizygous intragenic duplication of ~43.6 kb in ATRX, detected by research genome sequencing following non-diagnostic clinical testing. RNA sequencing and DNA methylation episignature analyses were central in variant interpretation, and this duplication was subsequently interpreted as disease-causing. This represents the smallest reported tandem duplication within ATRX associated with disease. This case demonstrates the diagnostic utility of integrating multiple omics technologies, which can ultimately lead to a definitive diagnosis for rare disease patients.

DOI: https://doi.org/10.1038/s10038-023-01203-8
Nat Commun. 2023 Oct 30. 14(1): 6900

DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.

Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy.

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

DOI: https://doi.org/10.1038/s41467-023-42521-x
bioRxiv. 2023 Oct 20. pii: 2023.10.18.562852. [Epub ahead of print]

Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan.

Ewa K Bomba-Warczak, Karen M Velez, Luhan T Zhou, Christelle Guillermier, Seby Edassery, Matthew Steinhauser, Jeffrey N Savas, Francesca E Duncan.

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues.
One sentence summary: Exceptionally long-lived macromolecules in mammalian ovaries and oocytes as pillars for lifelong reproductive health span.

DOI: https://doi.org/10.1101/2023.10.18.562852
J Phys Chem B. 2023 Nov 03.

ATP-Bound State of the Uncoupling Protein 1 (UCP1) from Molecular Simulations.

Luise Jacobsen, Laura Lydersen, Himanshu Khandelia.

The uncoupling protein 1 (UCP1) dissipates the transmembrane (TM) proton gradient in the inner mitochondrial membrane (IMM) by leaking protons across the membrane and producing heat in the process. Such a nonshivering production of heat in the brown adipose tissue can combat obesity-related diseases. UCP1-associated proton leak is activated by free fatty acids and inhibited by purine nucleotides. The mechanism of proton leak and the binding sites of the activators (fatty acids) remain unknown, while the binding site of the inhibitors (nucleotides) was described recently. Using molecular dynamics simulations, we generated a conformational ensemble of UCP1. Using metadynamics-based free energy calculations, we obtained the most likely ATP-bound conformation of UCP1. Our conformational ensemble provides a molecular basis for a breadth of prior biochemical data available for UCP1. Based on the simulations, we make the following testable predictions about the mechanisms of activation of proton leak and proton leak inhibition by ATP: (1) R277 plays the dual role of stabilizing ATP at the binding site for inhibition and acting as a proton surrogate for D28 in the absence of a proton during proton transport, (2) the binding of ATP to UCP1 is mediated by residues R84, R92, R183, and S88, (3) R92 shuttles ATP from the E191-R92 gate in the intermembrane space to the nucleotide binding site and serves to increase ATP affinity, (4) ATP can inhibit proton leak by controlling the ionization states of matrix facing lysine residues such as K269 and K56, and (5) fatty acids can bind to UCP1 from the IMM either via the cavity between TM1 and TM2 or between TM5 and TM6. Our simulations set the platform for future investigations into the proton transport and inhibition mechanisms of UCP1.

DOI: https://doi.org/10.1021/acs.jpcb.3c03473
bioRxiv. 2023 Oct 21. pii: 2023.10.18.562964. [Epub ahead of print]

Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes.

Marija Orlic-Milacic, Karen Rothfels, Lisa Matthews, Adam Wright, Bijay Jassal, Veronica Shamovsky, Quang Trinh, Marc Gillespie, Cristoffer Sevilla, Krishna Tiwari, Eliot Ragueneau, Chuqiao Gong, Ralf Stephan, Bruce May, Robin Haw, Joel Weiser, Deidre Beavers, Patrick Conley, Henning Hermjakob, Lincoln D Stein, Peter D'Eustachio, Guanming Wu.

Disease variant annotation in the context of biological reactions and pathways can provide a standardized overview of molecular phenotypes of pathogenic mutations that is amenable to computational mining and mathematical modeling. Reactome, an open source, manually curated, peer-reviewed database of human biological pathways, provides annotations for over 4000 disease variants of close to 400 genes in the context of ∼800 disease reactions constituting ∼400 disease pathways. Functional annotation of disease variants proceeds from normal gene functions, through disease variants whose divergence from normal molecular behaviors has been experimentally verified, to extrapolation from molecular phenotypes of characterized variants to variants of unknown significance using criteria of the American College of Medical Genetics and Genomics (ACMG). Reactome's pathway-based, reaction-specific disease variant dataset and data model provide a platform to infer pathway output impacts of numerous human disease variants and model organism orthologs, complementing computational predictions of variant pathogenicity.

DOI: https://doi.org/10.1101/2023.10.18.562964
Circulation. 2023 10 31.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

Feng Gao, Tian Liang, Yao Wei Lu, Linbin Pu, Xuyang Fu, Xiaoxuan Dong, Tingting Hong, Feng Zhang, Ning Liu, Yuxia Zhou, Hongkun Wang, Ping Liang, Yuxuan Guo, Hong Yu, Wei Zhu, Xinyang Hu, Hong Chen, Bin Zhou, William T Pu, John D Mably, Jian'an Wang, Da-Zhi Wang, Jinghai Chen.

   BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation.
METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed.
RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 (activating transcription factor 4) regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes.
CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

Keywords:  cell division; myocardial infarction; transcription factors

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.061192
Emerg Top Life Sci. 2023 Oct 31. pii: ETLS20230074. [Epub ahead of print]

Advances in the discovery and analyses of human tandem repeats.

Mark J P Chaisson, Arvis Sulovari, Paul N Valdmanis, Danny E Miller, Evan E Eichler.

  Long-read sequencing platforms provide unparalleled access to the structure and composition of all classes of tandemly repeated DNA from STRs to satellite arrays. This review summarizes our current understanding of their organization within the human genome, their importance with respect to disease, as well as the advances and challenges in understanding their genetic diversity and functional effects. Novel computational methods are being developed to visualize and associate these complex patterns of human variation with disease, expression, and epigenetic differences. We predict accurate characterization of this repeat-rich form of human variation will become increasingly relevant to both basic and clinical human genetics.

Keywords:  bioinformatics; disease; sequencing; tandem repeats; visualization

DOI:  https://doi.org/10.1042/ETLS20230074
Cell Rep. 2023 Nov 01. pii: S2211-1247(23)01226-3. [Epub ahead of print]42(11): 113214

LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.

Haoran Sun, Jun Zhang, Qianqian Ye, Ting Jiang, Xueling Liu, Xiaoyang Zhang, Fanyu Zeng, Jie Li, Yue Zheng, Xianlin Han, Chuan Su, Yuguang Shi.

  Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

Keywords:  CP: Cell biology; LPGAT1; MEGDEL syndrome; mitochondrial dysfunction; phosphatidylglycerol; prohibitin/TIM complex

DOI:  https://doi.org/10.1016/j.celrep.2023.113214
Curr Med Chem. 2023 Oct 26.

The Role of Mitokines in Diabetic Nephropathy.

Ming Yang, Wei Chen, Liyu He, Xi Wang, Di Liu, Li Xiao, Lin Sun.

  Diabetic nephropathy (DN) has gradually become one of the main causes of end-stage renal disease (ESRD). However, there is still a lack of effective preventive measures to delay its progression. As the energy factory in the cell, mitochondria play an irreplaceable role in maintaining cell homeostasis. Interestingly, recent studies have shown that in addition to maintaining homeostasis in cells in which mitochondria reside, when mitochondrial perturbations occur in one tissue, distal tissues can also sense and act through mitochondrial stress response pathways through a group of proteins or peptides called "mitokines". Here, we reviewed the mitokines that have been found thus far and summarized their research progress in DN. Finally, we explored the possibility of mitokines as potential therapeutic targets for DN.

Keywords:  Diabetic nephropathy (DN); FGF21; Humanin; MOTS-c; Mitokines; mitochondrial stress ?

DOI:  https://doi.org/10.2174/0109298673255403230919061828
Biochim Biophys Acta Mol Cell Res. 2023 Oct 26. pii: S0167-4889(23)00188-X. [Epub ahead of print] 119615

Two functionally different mitochondrial phosphate carriers support Drosophila melanogaster OXPHOS throughout distinct developmental stages.

Rosita Curcio, Luca Frattaruolo, Federica Marra, Graziano Pesole, Angelo Vozza, Anna Rita Cappello, Marco Fiorillo, Graziantonio Lauria, Amer Ahmed, Giuseppe Fiermonte, Loredana Capobianco, Vincenza Dolce.



Keywords:  CG4994; CG9090; Drosophila melanogaster; Mitochondrial phosphate carrier; OXPHOS genes; SLC25 solute carrier

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119615
Kidney Dis (Basel). 2023 Aug;9(4): 254-264

Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis.

Yuting Li, Jiaojiao Fan, Wenping Zhu, Yujia Niu, Mengqiu Wu, Aihua Zhang.

   Background: Podocytes are essential components of the glomerular filtration barrier and essential for the proper filtration function of the glomerulus. Podocyte injury under various stress conditions is the primary pathogenesis and key determinant of focal segmental glomerulosclerosis (FSGS) with prominent clinical manifestations of proteinuria or nephrotic syndrome.
Summary: Under physiological conditions, a highly coordinated mitochondrial quality control system, including antioxidant defenses, mitochondrial dynamics (fusion, fission, and mitophagy), and mitochondrial biogenesis, guarantees the sophisticated structure and various functions of podocytes. However, under FSGS pathological conditions, mitochondria encounter oxidative stress, dynamics disturbances, and defective mitochondrial biogenesis. Moreover, mutations in mitochondrial DNA and mitochondria-related genes are also strongly associated with FSGS. Based on these pieces of evidence, bioactive agents that function to relieve mitochondrial oxidative stress and promote mitochondrial biogenesis have been proven effective in preclinical FSGS models. Targeting the mitochondrial network is expected to provide new therapeutic strategies for the treatment of FSGS and delay its progression to end-stage renal disease.
Key Messages: Mitochondrial dysfunction plays a key role in podocyte injury and FSGS progression. This review summarized recent advances in the study of mitochondrial homeostatic imbalance and dysfunction in FSGS and discussed the potential of mitochondria-targeted therapeutics in improving FSGS and retarding its progression to end-stage renal disease.

Keywords:  Focal segmental glomerulosclerosis; Mitochondria; Podocyte

DOI:  https://doi.org/10.1159/000530344
Sci Adv. 2023 11 03. 9(44): eadh2584

UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

Franziska Pohl, Allison L Germann, Jack Mao, Sydney Hou, Bayode Bakare, Paul Kong Thoo Lin, Kyari Yates, Michael L Nonet, Gustav Akk, Kerry Kornfeld, Jason M Held.

The γ-aminobutyric acid-mediated (GABAergic) system participates in many aspects of organismal physiology and disease, including proteostasis, neuronal dysfunction, and life-span extension. Many of these phenotypes are also regulated by reactive oxygen species (ROS), but the redox mechanisms linking the GABAergic system to these phenotypes are not well defined. Here, we report that GABAergic redox signaling cell nonautonomously activates many stress response pathways in Caenorhabditis elegans and enhances vulnerability to proteostasis disease in the absence of oxidative stress. Cell nonautonomous redox activation of the mitochondrial unfolded protein response (mitoUPR) proteostasis network requires UNC-49, a GABAA receptor that we show is activated by hydrogen peroxide. MitoUPR induction by a spinocerebellar ataxia type 3 (SCA3) C. elegans neurodegenerative disease model was similarly dependent on UNC-49 in C. elegans. These results demonstrate a multi-tissue paradigm for redox signaling in the GABAergic system that is transduced via a GABAA receptor to function in cell nonautonomous regulation of health, proteostasis, and disease.

DOI: https://doi.org/10.1126/sciadv.adh2584
Cell Metab. 2023 Oct 20. pii: S1550-4131(23)00377-7. [Epub ahead of print]

The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.

Panu K Luukkonen, Kimmo Porthan, Noora Ahlholm, Fredrik Rosqvist, Sylvie Dufour, Xian-Man Zhang, Tiina E Lehtimäki, Wenla Seppänen, Marju Orho-Melander, Leanne Hodson, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen.

  The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.

Keywords:  GDF-15; NAD+; NADH; NAFLD; NASH; ketogenic diet; mitochondrial dysfunction; patatin-like phospholipase domain containing protein 3; redox; reductive stress

DOI:  https://doi.org/10.1016/j.cmet.2023.10.008
PLoS One. 2023 ;18(11): e0286660

Real-time resolution studies of the regulation of pyruvate-dependent lactate metabolism by hexokinases in single cells.

Scott John, Guillaume Calmettes, Shili Xu, Bernard Ribalet.

Lactate is a mitochondrial substrate for many tissues including neuron, muscle, skeletal and cardiac, as well as many cancer cells, however little is known about the processes that regulate its utilization in mitochondria. Based on the close association of Hexokinases (HK) with mitochondria, and the known cardio-protective role of HK in cardiac muscle, we have investigated the regulation of lactate and pyruvate metabolism by hexokinases (HKs), utilizing wild-type HEK293 cells and HEK293 cells in which the endogenous HKI and/or HKII have been knocked down to enable overexpression of wild type and mutant HKs. To assess the real-time changes in intracellular lactate levels the cells were transfected with a lactate specific FRET probe. In the HKI/HKII double knockdown cells, addition of extracellular pyruvate caused a large and sustained decrease in lactate. This decrease was rapidly reversed upon inhibition of the malate aspartate shuttle by aminooxyacetate, or inhibition of mitochondrial oxidative respiration by NaCN. These results suggest that in the absence of HKs, pyruvate-dependent activation of the TCA cycle together with the malate aspartate shuttle facilitates lactate transformation into pyruvate and its utilization by mitochondria. With replacement by overexpression of HKI or HKII the cellular response to pyruvate and NaCN was modified. With either hexokinase present, both the decrease in lactate due to the addition of pyruvate and the increase following addition of NaCN were either transient or suppressed altogether. Blockage of the pentose phosphate pathway with the inhibitor 6-aminonicotinamide (6-AN), abolished the effects of HK replacement. These results suggest that blocking of the malate aspartate shuttle by HK may involve activation of the pentose phosphate pathway and increased NADPH production.

DOI: https://doi.org/10.1371/journal.pone.0286660
Mol Genet Metab. 2023 Oct 26. pii: S1096-7192(23)00345-1. [Epub ahead of print] 107715

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Jennifer L Goldstein, Jennifer McGlaughon, Dona Kanavy, Shelly Goomber, Yinghong Pan, Brett Deml, Taraka Donti, Liz Kearns, Bryce A Seifert, Miriam Schachter, Rachel G Son, Courtney Thaxton, Rupa Udani, Deeksha Bali, Heather Baudet, Michele Caggana, Christina Hung, Lianna Kyriakopoulou, Lynne Rosenblum, Robert Steiner, Filippo Pinto E Vairo, Yang Wang, Michael Watson, Raquel Fernandez, Meredith Weaver, Lorne Clarke, Catherine Rehder.

  Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA. Variant classification can play an important role in confirming the diagnosis of Pompe disease as well as in the identification of carriers. Furthermore, since the inclusion of Pompe disease on the Recommended Uniform Screening Panel (RUSP) for newborns in the USA in 2015, the addition of molecular genetic testing has become an important component in the interpretation of newborn screening results, particularly for asymptomatic individuals. To date, the LD VCEP has submitted classifications and supporting data on 243 GAA variants to public databases, specifically ClinVar and the ClinGen Evidence Repository. Here, we describe the ACMG/AMP criteria specification process for GAA, an update of the GAA-specific variant classification guidelines, and comparison of the ClinGen LD VCEP's GAA variant classifications with variant classifications submitted to ClinVar. The LD VCEP has added to the publicly available knowledge on the pathogenicity of variants in GAA by increasing the number of expert-curated GAA variants present in ClinVar, and aids in resolving conflicting classifications and variants of uncertain clinical significance.

Keywords:  ClinGen variant curation expert panel; ClinVar; GAA; Glycogen storage disease type II; Pompe disease; Variant classification

DOI:  https://doi.org/10.1016/j.ymgme.2023.107715
Anal Chem. 2023 Oct 31.

NMR-Based Mitochondria Metabolomic Profiling: A New Approach To Reveal Cancer-Associated Alterations.

Inés Domingo-Ortí, Patricia Ferrer-Torres, Ana Armiñán, María J Vicent, Antonio Pineda-Lucena, Martina Palomino-Schätzlein.

Studying metabolism may assist in understanding the relationship between normal and dysfunctional mitochondrial activity and various diseases, such as neurodegenerative, cardiovascular, autoimmune, psychiatric, and cancer. Nuclear magnetic resonance-based metabolomics represents a powerful method to characterize the chemical content of complex samples and has been successfully applied to studying a range of conditions. However, an optimized methodology is lacking for analyzing isolated organelles, such as mitochondria. In this study, we report the development of a protocol to metabolically profile mitochondria from healthy, tumoral, and metastatic tissues. Encouragingly, this approach provided quantitative information about up to 45 metabolites in one comprehensive and robust analysis. Our results revealed significant differences between whole-cell and mitochondrial metabolites, which supports a more refined approach to metabolic analysis. We applied our optimized methodology to investigate aggressive and metastatic breast cancer in mouse tissues, discovering that lung mitochondria exhibit an altered metabolic fingerprint. Specific amino acids, organic acids, and lipids showed significant increases in levels when compared with mitochondria from healthy tissues. Our optimized methodology could promote a better understanding of the molecular mechanisms underlying breast cancer aggressiveness and mitochondrial-related diseases and support the optimization of new advanced therapies.

DOI: https://doi.org/10.1021/acs.analchem.3c02432
bioRxiv. 2023 Oct 24. pii: 2023.10.16.562114. [Epub ahead of print]

OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records.

Qingwen Chen, Varun B Dwaraka, Natàlia Carreras-Gallo, Kevin Mendez, Yulu Chen, Sofina Begum, Priyadarshini Kachroo, Nicole Prince, Hannah Went, Tavis Mendez, Aaron Lin, Logan Turner, Mahdi Moqri, Su H Chu, Rachel S Kelly, Scott T Weiss, Nicholas J W Rattray, Vadim N Gladyshev, Elizabeth Karlson, Craig Wheelock, Ewy A Mathé, Amber Dahlin, Michae J McGeachie, Ryan Smith, Jessica A Lasky-Su.

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype, EMRAge , that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.

DOI: https://doi.org/10.1101/2023.10.16.562114
Sci Rep. 2023 Oct 30. 13(1): 18600

Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.

Anastasia Schultz, Shun-Yun Cheng, Emily Kirchner, Stephanann Costello, Heini Miettinen, Marta Chaverra, Colin King, Lynn George, Xin Zhao, Jana Narasimhan, Marla Weetall, Susan Slaugenhaupt, Elisabetta Morini, Claudio Punzo, Frances Lefcort.

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.

DOI: https://doi.org/10.1038/s41598-023-45376-w
Front Physiol. 2023 ;14 1261204

The regulatory role of adipocyte mitochondrial homeostasis in metabolism-related diseases.

Hongbing Song, Xiaohan Zhang, Jing Wang, Yanling Wu, Taimin Xiong, Jieqiong Shen, Ruiyi Lin, Tianfang Xiao, Weimin Lin.

  Adipose tissue is the most important energy storage organ in the body, maintaining its normal energy metabolism function and playing a vital role in keeping the energy balance of the body to avoid the harm caused by obesity and a series of related diseases resulting from abnormal energy metabolism. The dysfunction of adipose tissue is closely related to the occurrence of diseases related to obesity metabolism. Among various organelles, mitochondria are the main site of energy metabolism, and mitochondria maintain their quality through autophagy, biogenesis, transfer, and dynamics, which play an important role in maintaining metabolic homeostasis of adipocytes. On the other hand, mitochondria have mitochondrial genomes which are vulnerable to damage due to the lack of protective structures and their proximity to sites of reactive oxygen species generation, thus affecting mitochondrial function. Notably, mitochondria are closely related to other organelles in adipocytes, such as lipid droplets and the endoplasmic reticulum, which enhances the function of mitochondria and other organelles and regulates energy metabolism processes, thus reducing the occurrence of obesity-related diseases. This article introduces the structure and quality control of mitochondria in adipocytes and their interactions with other organelles in adipocytes, aiming to provide a new perspective on the regulation of mitochondrial homeostasis in adipocytes on the occurrence of obesity-related diseases, and to provide theoretical reference for further revealing the molecular mechanism of mitochondrial homeostasis in adipocytes on the occurrence of obesity-related diseases.

Keywords:  adipocyte; adipose tissue; metabolic syndrome; mitochondria; obesity

DOI:  https://doi.org/10.3389/fphys.2023.1261204