bims-mitdis 2022-12-25 papers

bims-mitdis

Biomed News

on Mitochondrial disorders

Issue of 2022–12–25
thirty-two papers selected by
Catalina Vasilescu, Helmholz Munich

Moms' mitochondria may refresh cells in sick kids.
The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease.
Mitochondrial Ultrastructural Defects in NDUFS3-Related Disorder.
Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases.
Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons.
Mitochondria Clumping vs. Mitochondria Fusion in CMT2A Diseases.
The Therapeutic Strategies Targeting Mitochondrial Metabolism in Cardiovascular Disease.
Live-cell imaging and analysis of actin-mediated mitochondrial fission.
Mitochondria in Early Life.
Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance.
Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes.
Mitochondrial signaling on innate immunity activation in Parkinson disease.
Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches.
Childhood-Onset Leber Hereditary Optic Neuropathy - Clinical and Prognostic Insights.
DELE1 is protective for mitochondrial cardiomyopathy.
Exercise and mitochondrial mechanisms in patients with sarcopenia.
Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.
Hepatic PLIN5 Deficiency Impairs Lipogenesis through Mitochondrial Dysfunction.
Clinical Phenotype of FASTKD2 Mutation.
Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.
Chronic progressive external ophthalmoplegia plus syndrome due to Homozygous Missense Variant in TOP3A gene.
Rapid Targeted Sequencing Using Dried Blood Spot Samples for Patients With Suspected Actionable Genetic Diseases.
Nano3P-seq: transcriptome-wide analysis of gene expression and tail dynamics using end-capture nanopore cDNA sequencing.
Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts.
The Pathophysiological Significance of "Mitochondrial Ejection" from Cells.
Single-read tRNA-seq analysis reveals coordination of tRNA modification and aminoacylation and fragmentation.
The unbroken Krebs cycle. Hormonal-like regulation and mitochondrial signaling to control mitophagy and prevent cell death.
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.
Single-cell transcriptomics for the assessment of cardiac disease.
A Review on Advanced CRISPR-Based Genome-Editing Tools: Base Editing and Prime Editing.
Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives.
Ablating all mitochondrial protein-coding genes.

Science. 2022 Dec 23. 378(6626): 1267

Moms' mitochondria may refresh cells in sick kids.

Mitch Leslie.

Technique is designed to treat mitochondrial disease.

DOI: https://doi.org/10.1126/science.adg3936
Genes (Basel). 2022 Dec 09. pii: 2319. [Epub ahead of print]13(12):

The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease.

Christina Del Greco, Anthony Antonellis.

  Aminoacyl-tRNA synthetases (ARSs) are highly conserved essential enzymes that charge tRNA with cognate amino acids-the first step of protein synthesis. Of the 37 nuclear-encoded human ARS genes, 17 encode enzymes are exclusively targeted to the mitochondria (mt-ARSs). Mutations in nuclear mt-ARS genes are associated with rare, recessive human diseases with a broad range of clinical phenotypes. While the hypothesized disease mechanism is a loss-of-function effect, there is significant clinical heterogeneity among patients that have mutations in different mt-ARS genes and also among patients that have mutations in the same mt-ARS gene. This observation suggests that additional factors are involved in disease etiology. In this review, we present our current understanding of diseases caused by mutations in the genes encoding mt-ARSs and propose explanations for the observed clinical heterogeneity.

Keywords:  aminoacyl-tRNA synthetases; mitochondrial biology; neurological disease; protein synthesis; tRNA biology

DOI:  https://doi.org/10.3390/genes13122319
J Pediatr Neurosci. 2021 Oct-Dec;16(4):16(4): 299-302

Mitochondrial Ultrastructural Defects in NDUFS3-Related Disorder.

Debopam Samanta, Aravindhan Veerapandiyan, Thomas A Burrow, Murat Gokden.

  Complex I, the largest multisubunit enzyme complex of the respiratory chain, has a vital role in the energy production of the cell, and the clinical spectrum of complex I deficiency varies from severe lactic acidosis in infants to muscle weakness in adults. Pathogenic variants of NDUFS3 (constitutes the catalytic core of the complex I) have been reported in a small number of patients with variable phenotypes. We describe a girl with a history of infantile-onset nonepileptic myoclonus, who developed myopathy at the age of 2 years. Next-generation sequencing revealed compound heterozygous for two variants in the NDUSF3 gene. The electron-microscopic study of the skeletal muscle showed an increase in the number of mitochondria inside the myofibers; mitochondria were variably enlarged with some irregularity and were aligned perpendicular to the myofibrils in a stacked-up manner. This is the first description of mitochondrial ultrastructural abnormality in an individual with NDUFS3-related disorder.

Keywords:  Complex I; NDUFS3; mitochondria; myoclonus; myopathy

DOI:  https://doi.org/10.4103/jpn.JPN_182_20
Int J Mol Sci. 2022 Dec 16. pii: 16053. [Epub ahead of print]23(24):

Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases.

Yu Liu, Yuejia Huang, Chong Xu, Peng An, Yongting Luo, Lei Jiao, Junjie Luo, Yongzhi Li.

  High mortality rates due to cardiovascular diseases (CVDs) have attracted worldwide attention. It has been reported that mitochondrial dysfunction is one of the most important mechanisms affecting the pathogenesis of CVDs. Mitochondrial DNA (mtDNA) mutations may result in impaired oxidative phosphorylation (OXPHOS), abnormal respiratory chains, and ATP production. In dysfunctional mitochondria, the electron transport chain (ETC) is uncoupled and the energy supply is reduced, while reactive oxygen species (ROS) production is increased. Here, we discussed and analyzed the relationship between mtDNA mutations, impaired mitophagy, decreased OXPHOS, elevated ROS, and CVDs from the perspective of mitochondrial dysfunction. Furthermore, we explored current potential therapeutic strategies for CVDs by eliminating mtDNA mutations (e.g., mtDNA editing and mitochondrial replacement), enhancing mitophagy, improving OXPHOS capacity (e.g., supplement with NAD+, nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nano-drug delivery), and reducing ROS (e.g., supplement with Coenzyme Q10 and other antioxidants), and dissected their respective advantages and limitations. In fact, some therapeutic strategies are still a long way from achieving safe and effective clinical treatment. Although establishing effective and safe therapeutic strategies for CVDs remains challenging, starting from a mitochondrial perspective holds bright prospects.

Keywords:  cardiovascular disease; mitochondrial DNA mutation; mitochondrial dysfunction; mitophagy; oxidative phosphorylation; reactive oxygen species; therapeutic strategy

DOI:  https://doi.org/10.3390/ijms232416053
Front Mol Neurosci. 2022 ;15 966209

Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons.

Lisa Schwarz, Karan Sharma, Lorenzo D Dodi, Lara-Sophie Rieder, Petra Fallier-Becker, Nicolas Casadei, Julia C Fitzgerald.

  The Rho GTPase Miro1, located at the mitochondrial outer membrane is known to properly distribute mitochondria to synapses, aid calcium buffering and initiate PINK1-Parkin mediated mitophagy. Several heterozygous RHOT1/Miro1 variants were identified in sporadic Parkinson's disease patients. Miro1 R272Q is located within a calcium binding domain, but the functional outcome of this point mutation and its contribution to the development of disease are unclear. To address this, we introduced a heterozygous RHOT1/Miro1 R272Q point mutation in healthy induced pluripotent stem cells. In dopaminergic neurons, Miro1 R272Q does not affect Miro1 protein levels, CCCP-induced mitophagy, nor mitochondrial movement yet causes the fragmentation of mitochondria with reduction of cristae and ATP5A. Inhibition of the mitochondrial calcium uniporter phenocopied Miro1 R272Q cytosolic calcium response to Thapsigargin in active neurons, a similar effect was observed during the calcium buffering phase in Miro1 knockdown neuroblastoma cells. Altered mitochondrial calcium regulation is associated with reduced mitochondrial respiration and reduced catecholamine neurotransmitter uptake. Synaptic changes are not coupled to dopamine distribution or dopamine transporters but are linked to Miro1 R272Q-related calcium handling via the mitochondria concomitant with defective dopamine regulation at the mitochondrial surface by monoamine oxidase. We conclude that the Miro1 R272Q heterozygous point mutation dampens mitochondrial-calcium regulation and mitochondrial capacity via events at the outer membrane that are sufficient to disrupt dopaminergic function.

Keywords:  Miro1; Parkinson’s disease; calcium; dopaminergic neuron; mitochondria

DOI:  https://doi.org/10.3389/fnmol.2022.966209
Life (Basel). 2022 Dec 15. pii: 2110. [Epub ahead of print]12(12):

Mitochondria Clumping vs. Mitochondria Fusion in CMT2A Diseases.

Antonietta Franco, Caroline E Walton, Xiawei Dang.

  Phenotypic variations in Charcot-Marie-Tooth disease type 2A (CMT2A) result from the many mutations in the mitochondrial fusion protein, mitofusin 2 (MFN2). While the GTPase domain mutations of MFN2 lack the ability to hydrolyze GTP and complete mitochondrial fusion, the mechanism of dysfunction in HR1 domain mutations has yet to be explored. Using Mfn1/Mfn2 double null cells and Mfn2 knock out (KO) fibroblasts, we measured the ability of this variant protein to change conformations and hydrolyze GTP. We found that a mutation in the HR1 domain (M376A) of MFN2 results in conformational change dysfunction while maintaining GTPase ability. Prolonged exposure to mitofusin agonist MiM 111 reverses mitochondrial fusion dysfunction in the HR1 mutant through encouraging an open conformation, resulting in a potential therapeutic model in this variant. Herein, we describe a novel mechanism of dysfunction in MFN2 variants through exploring domain-specific mitochondrial characteristics leading to CMT2A.

Keywords:  Charcot-Marie-Tooth disease type 2A; mitochondria fitness; mitochondria fusion defects; mitofusin 2

DOI:  https://doi.org/10.3390/life12122110
Pharmaceutics. 2022 Dec 09. pii: 2760. [Epub ahead of print]14(12):

The Therapeutic Strategies Targeting Mitochondrial Metabolism in Cardiovascular Disease.

Xiaoyang Huang, Zhenhua Zeng, Siqi Li, Yufei Xie, Xiaoyong Tong.

  Cardiovascular disease (CVD) is a group of systemic disorders threatening human health with complex pathogenesis, among which mitochondrial energy metabolism reprogramming has a critical role. Mitochondria are cell organelles that fuel the energy essential for biochemical reactions and maintain normal physiological functions of the body. Mitochondrial metabolic disorders are extensively involved in the progression of CVD, especially for energy-demanding organs such as the heart. Therefore, elucidating the role of mitochondrial metabolism in the progression of CVD is of great significance to further understand the pathogenesis of CVD and explore preventive and therapeutic methods. In this review, we discuss the major factors of mitochondrial metabolism and their potential roles in the prevention and treatment of CVD. The current application of mitochondria-targeted therapeutic agents in the treatment of CVD and advances in mitochondria-targeted gene therapy technologies are also overviewed.

Keywords:  cardiovascular disease; gene therapy; mitochondria-targeted therapy; mitochondrial DNA; mitochondrial calcium; mitochondrial dynamics; mitochondrial metabolism; reactive oxygen species

DOI:  https://doi.org/10.3390/pharmaceutics14122760
STAR Protoc. 2022 Dec 20. pii: S2666-1667(22)00838-3. [Epub ahead of print]4(1): 101958

Live-cell imaging and analysis of actin-mediated mitochondrial fission.

Daisuke Shimura, Robin M Shaw.

  Current approaches, such as fixed-cell imaging or single-snapshot imaging, are insufficient to capture cytoskeleton-mediated mitochondrial fission. Here, we present a protocol to capture actin-mediated mitochondrial fission using high-resolution time-lapse imaging. We describe steps starting from cell preparation and mitochondria labeling through to live-cell imaging and final analysis. This approach is also applicable for analysis of multiple cytoskeleton-mediated organelle events such as vesicle trafficking, membrane fusion, and endocytic events in live cells. For complete details on the use and execution of this protocol, please refer to Shimura et al. (2021).1.

Keywords:  Cell Biology; Microscopy; Molecular Biology

DOI:  https://doi.org/10.1016/j.xpro.2022.101958
Curr Pediatr Rev. 2022 Dec 21.

Mitochondria in Early Life.

Ling He, Akhil Maheshwari.

  Mitochondria are highly-dynamic, membrane-bound organelles that generate most of the chemical energy needed to power the biochemical reactions in eukaryotic cells. These organelles also communicate with the nucleus and other cellular structures to help maintain somatic homeostasis, allow cellular adaptation to stress, and help maintain the developmental trajectory. Mitochondria also perform numerous other functions to support metabolic, energetic, and epigenetic regulation in our cells. There is increasing information on various disorders caused by defects in intrinsic mitochondrial or supporting nuclear genes in different organ systems. In this review, we have summarized the ultrastructural morphology, structural components, our current understanding of the evolution, biogenesis, dynamics, function, clinical manifestations of mitochondrial dysfunction, and future possibilities. The implications of deficits in mitochondrial dynamics and signaling for embryo viability and offspring health are also explored. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.

Keywords:  Archezoan; Biogenesis; Epigenetic; Inner membrane; Intermembrane space; Matrix; Mitochondrial DNA; Mitochondrial function; Mitochondrion-related organelles; Neonate; Outer membrane

DOI:  https://doi.org/10.2174/1573396319666221221110728
J Neurochem. 2022 Dec 23.

Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance.

João Victor Cabral-Costa, Carlos Vicente-Gutiérrez, Jesús Agulla, Rebeca Lapresa, John W Elrod, Ángeles Almeida, Juan P Bolaños, Alicia J Kowaltowski.

  Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUc), while efflux occurs mainly through the mitochondrial Na+ /Ca2+ exchanger (NCLX). RNAseq database repository searches led us to identify the Nclx transcript as highly enriched in astrocytes when compared to neurons. To assess the role of NCLX in mouse primary culture astrocytes, we inhibited its function both pharmacologically or genetically. This resulted in re-shaping of cytosolic Ca2+ signaling and a metabolic shift that increased glycolytic flux and lactate secretion in a Ca2+ -dependent manner. Interestingly, in vivo genetic deletion of NCLX in hippocampal astrocytes improved cognitive performance in behavioral tasks, whereas hippocampal neuron-specific deletion of NCLX impaired cognitive performance. These results unveil a role for NCLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition.

Keywords:  NCLX; astrocyte; brain metabolism; calcium transport; energy metabolism; glycolysis; lactate; metabolic regulation; mitochondrial metabolism; sodium transport; sodium-calcium exchange

DOI:  https://doi.org/10.1111/jnc.15745
Antioxidants (Basel). 2022 Nov 22. pii: 2308. [Epub ahead of print]11(12):

Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes.

Sining Wang, Akash Jain, Noelle Alexa Novales, Audrey N Nashner, Fiona Tran, Catherine F Clarke.

  Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ10 deficiency can arise from mutations in any of the COQ genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the COQ3-COQ7 and COQ9 gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as Saccharomyces cerevisiae are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ10 deficiency.

Keywords:  COQ genes; Missense3D; coenzyme Q; mitochondrial disease; primary CoQ deficiency; single nucleotide variants; ubiquinone

DOI:  https://doi.org/10.3390/antiox11122308
Curr Opin Neurobiol. 2022 Dec 16. pii: S0959-4388(22)00158-1. [Epub ahead of print]78 102664

Mitochondrial signaling on innate immunity activation in Parkinson disease.

João D Magalhães, Sandra Morais Cardoso.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (aSyn) in the nigrostriatal pathway that is followed by severe neuroinflammatory response. PD etiology is still puzzling; however, the mitocentric view might explain the vast majority of molecular findings not only in the brain, but also at systemic level. While neuronal degeneration is tightly associated with mitochondrial dysfunction, the causal role between aSyn accumulation and mitochondrial dysfunction still requires further investigation. Moreover, mitochondrial dysfunction can elicit an inflammatory response that may be transmitted locally but also in a long range through systemic circulation. Furthermore, mitochondrial-driven innate immune activation may involve the synthesis of antimicrobial peptides, of which aSyn poses as a good candidate. While there is still a need to clarify disease-elicited mechanisms and how aSyn has the ability to modulate mitochondrial and cellular dysfunction, recent studies provide insightful views on mitochondria-inflammation axis in PD etiology.

DOI: https://doi.org/10.1016/j.conb.2022.102664
Pharmaceutics. 2022 Nov 30. pii: 2657. [Epub ahead of print]14(12):

Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches.

Tanzeel Khan, Rashid Waseem, Zainy Zehra, Ayesha Aiman, Priyanka Bhardwaj, Jaoud Ansari, Md Imtaiyaz Hassan, Asimul Islam.

  Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria are considered a novel and promising therapeutic target for the diagnosis, treatment, and prevention of various human diseases including metabolic disorders, cancer, and neurodegenerative diseases. For mitochondria-targeted therapy, there is a need to develop an effective drug delivery approach, owing to the mitochondrial special bilayer structure through which therapeutic molecules undergo multiple difficulties in reaching the core. In recent years, various nanoformulations have been designed such as polymeric nanoparticles, liposomes, inorganic nanoparticles conjugate with mitochondriotropic moieties such as mitochondria-penetrating peptides (MPPs), triphenylphosphonium (TPP), dequalinium (DQA), and mitochondrial protein import machinery for overcoming barriers involved in targeting mitochondria. The current approaches used for mitochondria-targeted drug delivery have provided promising ways to overcome the challenges associated with targeted-drug delivery. Herein, we review the research from past years to the current scenario that has identified mitochondrial dysfunction as a major contributor to the pathophysiology of various diseases. Furthermore, we discuss the recent advancements in mitochondria-targeted drug delivery strategies for the pathologies associated with mitochondrial dysfunction.

Keywords:  drug delivery; mitochondrial dysfunction; nanoparticles; pathophysiology

DOI:  https://doi.org/10.3390/pharmaceutics14122657
Am J Ophthalmol. 2022 Dec 18. pii: S0002-9394(22)00501-3. [Epub ahead of print]

Childhood-Onset Leber Hereditary Optic Neuropathy - Clinical and Prognostic Insights.

Piero Barboni, Chiara La Morgia, Maria Lucia Cascavilla, Eun Hee Hong, Marco Battista, Anna Majander, Leonardo Caporali, Vincenzo Starace, Giulia Amore, Antonio Di Renzo, Michele Carbonelli, Paolo Nucci, Neringa Jurkute, Benson S Chen, Roberta Panebianco, Anna Maria De Negri, Federico Sadun, Vincenzo Parisi, Francesco Bandello, Alfredo A Sadun, Valerio Carelli, Patrick Yu-Wai-Man.

   PURPOSE: To investigate the clinical and molecular genetic features of childhood-onset Leber hereditary optic neuropathy (LHON) to gain a better understanding of the factors influencing the visual outcome in this atypical form of the disease.
DESIGN: Retrospective cohort study.
METHODS: We retrospectively included two cohorts of LHON patients with onset of visual loss before the age of 12 years old from Italy and the United Kingdom. Ophthalmological evaluation, including best-corrected visual acuity, orthoptic evaluation, slit-lamp biomicroscopy, visual field testing and optical coherence tomography (OCT) were considered. Patients were classified based both on the age of onset and the pattern of visual loss.
RESULTS: 68 PATIENTS WERE STRATIFIED BASED ON THE AGE OF ONSET OF VISUAL LOSS: GROUP 1 (< 3YRS): : 14 patients (20.6%); Group 2 (≥ 3 - < 9yrs): 27 patients (39.7%); and Group 3 (≥ 9 - ≤ 12yrs): 27 patients (39.7%). Patients in Group 2 achieved a better visual outcome compared with those in Group 3. Patients in Group 1 and Group 2 had better mean deviation on visual field testing compared with those in Group 3. The mean ganglion cell layer thickness on OCT was higher in Group 2 compared with those in Group 1 and Group 3. Patients were also categorized based on the pattern of visual loss as: Subacute Bilateral: 54 patients (66.7%); Insidious Bilateral: 14 patients (17.3%); Unilateral: 9 patients (11.1%); and Subclinical Bilateral: 4 patients (4.9%).
CONCLUSIONS: Children who lose vision from LHON before the age of 9 years old have a better visual prognosis compared with those who become affected in later years, likely representing a "form frustre" of the disease.

Keywords:  Leber hereditary optic neuropathy; childhood LHON; mitochondrial DNA; optic atrophy; optical coherence tomography

DOI:  https://doi.org/10.1016/j.ajo.2022.12.014
J Mol Cell Cardiol. 2022 Dec 17. pii: S0022-2828(22)00573-9. [Epub ahead of print]175 44-48

DELE1 is protective for mitochondrial cardiomyopathy.

Helen Huynh, Siting Zhu, Sharon Lee, Yutong Bao, Jing Pang, Anh Nguyen, Yusu Gu, Chao Chen, Kunfu Ouyang, Sylvia M Evans, Xi Fang.

  Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.

Keywords:  Dele1; Integrated stress response; Mitochondrial cardiomyopathy; Mitochondrial stress

DOI:  https://doi.org/10.1016/j.yjmcc.2022.12.003
Front Physiol. 2022 ;13 1040381

Exercise and mitochondrial mechanisms in patients with sarcopenia.

Hamed Alizadeh Pahlavani, Ismail Laher, Beat Knechtle, Hassane Zouhal.

  Sarcopenia is a severe loss of muscle mass and functional decline during aging that can lead to reduced quality of life, limited patient independence, and increased risk of falls. The causes of sarcopenia include inactivity, oxidant production, reduction of antioxidant defense, disruption of mitochondrial activity, disruption of mitophagy, and change in mitochondrial biogenesis. There is evidence that mitochondrial dysfunction is an important cause of sarcopenia. Oxidative stress and reduction of antioxidant defenses in mitochondria form a vicious cycle that leads to the intensification of mitochondrial separation, suppression of mitochondrial fusion/fission, inhibition of electron transport chain, reduction of ATP production, an increase of mitochondrial DNA damage, and mitochondrial biogenesis disorder. On the other hand, exercise adds to the healthy mitochondrial network by increasing markers of mitochondrial fusion and fission, and transforms defective mitochondria into efficient mitochondria. Sarcopenia also leads to a decrease in mitochondrial dynamics, mitophagy markers, and mitochondrial network efficiency by increasing the level of ROS and apoptosis. In contrast, exercise increases mitochondrial biogenesis by activating genes affected by PGC1-ɑ (such as CaMK, AMPK, MAPKs) and altering cellular calcium, ATP-AMP ratio, and cellular stress. Activation of PGC1-ɑ also regulates transcription factors (such as TFAM, MEFs, and NRFs) and leads to the formation of new mitochondrial networks. Hence, moderate-intensity exercise can be used as a non-invasive treatment for sarcopenia by activating pathways that regulate the mitochondrial network in skeletal muscle.

Keywords:  aging; exercise; mechanism; mitochondria; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2022.1040381
Molecules. 2022 Dec 09. pii: 8754. [Epub ahead of print]27(24):

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.

Sifan Wang, Yuanbo Kang, Ruifeng Wang, Junqi Deng, Yupei Yu, Jun Yu, Junpu Wang.

  NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

Keywords:  Leigh syndrome; NDUFS8; cancer; diabetes mellitus; metabolism; mitochondrial complex I

DOI:  https://doi.org/10.3390/molecules27248754
Int J Mol Sci. 2022 Dec 09. pii: 15598. [Epub ahead of print]23(24):

Hepatic PLIN5 Deficiency Impairs Lipogenesis through Mitochondrial Dysfunction.

Enxiang Zhang.

  Regulation of lipid droplets (LDs) metabolism is the core of controlling intracellular fatty acids (FAs) fluxes, and perilipin 5 (PLIN5) plays a key role in this process. Our previous studies have found that hepatic PLIN5 deficiency reduces LDs accumulation, but the trafficking of FAs produced from this pathway and the interaction between mitochondria and LDs in this process are largely unknown. Here, we found that the deficiency of PLIN5 decreases LDs accumulation by increasing FAs efflux. In addition, the decreased lipogenesis of PLIN5-deficient hepatocytes is accompanied by mitochondrial dysfunction, suggesting that PLIN5 plays an important role in mediating the interaction between LDs and mitochondria. Importantly, PLIN5 ablation negates oxidative capacity differences of peri-droplet and cytosolic mitochondria. In summary, these data indicate that PLIN5 plays a vital role in maintaining mitochondrial-mediated lipogenesis, which provides an important new perspective on the regulation of liver lipid storage and the relationship between PLIN5 and mitochondria.

Keywords:  LDs-mitochondria interaction; PLIN5; fatty acids; lipid droplets; lipogenesis

DOI:  https://doi.org/10.3390/ijms232415598
J Pediatr Neurosci. 2021 Oct-Dec;16(4):16(4): 319-322

Clinical Phenotype of FASTKD2 Mutation.

Ritesh Shah, Seema Balasubramaniam.

  Mitochondrial disorders (MIDs) are frequently multisystemic in nature and cause significant morbidity and mortality. Accurate assessment of mitochondrial disease prevalence has been difficult in the past. Primary MIDs are due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)-located genes. Here we report cases of two siblings who presented to the pediatric emergency department with status epilepticus. Initially, the elder sibling was treated for metabolic encephalopathy and viral encephalitis, during his admission to the hospital. On treatment with multiple antiepileptic drugs, the status epilepticus subsided. A provisional diagnosis of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes was made. Magnetic resonance imaging showed diffusion restriction in the left temporal lobe, insular cortex, and left lentiform nucleus, which completely resolved on follow-up after 1 month. His sudden demise in May 2019 due to status epilepticus, and a similar case presentation in his younger sibling, prompted us to do a genetic analysis test. The exome sequence revealed FASTKD2 mutation, a rare variant. This case report helps in increasing the awareness among the clinicians about the clinical presentation of FASTKD2 mutation case.

Keywords:  FASTKD2 mutation; MELAS; status epilepticus

DOI:  https://doi.org/10.4103/jpn.JPN_199_20
Sci Transl Med. 2022 Dec 21. 14(676): eabo3724

Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.

Elad Jacoby, Omer Bar-Yosef, Noah Gruber, Einat Lahav, Nira Varda-Bloom, Yoav Bolkier, Diana Bar, Moriya Ben-Yakir Blumkin, Sharon Barak, Etzyona Eisenstein, Jaana Ahonniska-Assa, Tamar Silberg, Tal Krasovsky, Orly Bar, Neta Erez, Bella Bielorai, Hana Golan, Benjamin Dekel, Michal J Besser, Gat Pozner, Hanan Khoury, Alan Jacobs, John Campbell, Eli Herskovitz, Noa Sher, Natalie Yivgi-Ohana, Yair Anikster, Amos Toren.

Patients with single large-scale mitochondrial DNA (mtDNA) deletion syndromes (SLSMDs) usually present with multisystemic disease, either as Pearson syndrome in early childhood or as Kearns-Sayre syndrome later in life. No disease-modifying therapies exist for SLSMDs. We have developed a method to enrich hematopoietic cells with exogenous mitochondria, and we treated six patients with SLSMDs through a compassionate use program. Autologous CD34+ hematopoietic cells were augmented with maternally derived healthy mitochondria, a technology termed mitochondrial augmentation therapy (MAT). All patients had substantial multisystemic disease involvement at baseline, including neurologic, endocrine, or renal impairment. We first assessed safety, finding that the procedure was well tolerated and that all study-related severe adverse events were either leukapheresis-related or related to the baseline disorder. After MAT, heteroplasmy decreased in the peripheral blood in four of the six patients. An increase in mtDNA content of peripheral blood cells was measured in all six patients 6 to 12 months after MAT as compared baseline. We noted some clinical improvement in aerobic function, measured in patients 2 and 3 by sit-to-stand or 6-min walk testing, and an increase in the body weight of five of the six patients suffering from very low body weight before treatment. Quality-of-life measurements as per caregiver assessment and physical examination showed improvement in some parameters. Together, this work lays the ground for clinical trials of MAT for the treatment of patients with mtDNA disorders.

DOI: https://doi.org/10.1126/scitranslmed.abo3724
Clin Genet. 2022 Dec 21.

Chronic progressive external ophthalmoplegia plus syndrome due to Homozygous Missense Variant in TOP3A gene.

Arnau Llauradó, Eulalia Rovira-Moreno, Marta Codina-Solà, Elena Martínez-Saez, Maria Salvadó, Daniel Sanchez-Tejerina, Javier Sotoca, Verónica López-Diego, Juan Luis Restrepo-Vera, Elena Garcia-Arumi, Raul Juntas-Morales.



Keywords:  Chronic progressive external ophthalmoplegia plus syndrome; Mitochondrial disease; Mitochondrial maintenance genes; TOP3A gene

DOI:  https://doi.org/10.1111/cge.14287
Ann Lab Med. 2023 May 01. 43(3): 280-289

Rapid Targeted Sequencing Using Dried Blood Spot Samples for Patients With Suspected Actionable Genetic Diseases.

Man Jin Kim, Soo Yeon Kim, Jin Sook Lee, Sanggoo Kang, Lae-Jeong Park, Wooyong Choi, Ju Yeol Jung, Taehyung Kim, Sung Sup Park, Jung Min Ko, Moon-Woo Seong, Jong Hee Chae.

   Background: New genome sequencing technologies with enhanced diagnostic efficiency have emerged. Rapid and timely diagnosis of treatable rare genetic diseases can alter their medical management and clinical course. However, multiple factors, including ethical issues, must be considered. We designed a targeted sequencing platform to avoid ethical issues and reduce the turnaround time.
Methods: We designed an automated sequencing platform using dried blood spot samples and a NEOseq_ACTION panel comprising 254 genes associated with Mendelian diseases having curable or manageable treatment options. Retrospective validation was performed using data from 24 genetically and biochemically confirmed patients. Prospective validation was performed using data from 111 patients with suspected actionable genetic diseases.
Results: In prospective clinical validation, 13.5% patients presented with medically actionable diseases, including short- or medium-chain acyl-CoA dehydrogenase deficiencies (N=6), hyperphenylalaninemia (N=2), mucopolysaccharidosis type IVA (N=1), alpha thalassemia (N=1), 3-methylcrotonyl-CoA carboxylase 2 deficiency (N=1), propionic acidemia (N=1), glycogen storage disease, type IX(a) (N=1), congenital myasthenic syndrome (N=1), and citrullinemia, type II (N=1). Using the automated analytic pipeline, the turnaround time from blood collection to result reporting was <4 days.
Conclusions: This pilot study evaluated the possibility of rapid and timely diagnosis of treatable rare genetic diseases using a panel designed by a multidisciplinary team. The automated analytic pipeline maximized the clinical utility of rapid targeted sequencing for medically actionable genes, providing a strategy for appropriate and timely treatment of rare genetic diseases.

Keywords:  Dried blood spot; High-throughput nucleotide sequencing; Inborn errors; Metabolism; Neonatal screening

DOI:  https://doi.org/10.3343/alm.2023.43.3.280
Nat Methods. 2022 Dec 19.

Nano3P-seq: transcriptome-wide analysis of gene expression and tail dynamics using end-capture nanopore cDNA sequencing.

Oguzhan Begik, Gregor Diensthuber, Huanle Liu, Anna Delgado-Tejedor, Cassandra Kontur, Adnan Muhammad Niazi, Eivind Valen, Antonio J Giraldez, Jean-Denis Beaudoin, John S Mattick, Eva Maria Novoa.

RNA polyadenylation plays a central role in RNA maturation, fate, and stability. In response to developmental cues, polyA tail lengths can vary, affecting the translation efficiency and stability of mRNAs. Here we develop Nanopore 3' end-capture sequencing (Nano3P-seq), a method that relies on nanopore cDNA sequencing to simultaneously quantify RNA abundance, tail composition, and tail length dynamics at per-read resolution. By employing a template-switching-based sequencing protocol, Nano3P-seq can sequence RNA molecule from its 3' end, regardless of its polyadenylation status, without the need for PCR amplification or ligation of RNA adapters. We demonstrate that Nano3P-seq provides quantitative estimates of RNA abundance and tail lengths, and captures a wide diversity of RNA biotypes. We find that, in addition to mRNA and long non-coding RNA, polyA tails can be identified in 16S mitochondrial ribosomal RNA in both mouse and zebrafish models. Moreover, we show that mRNA tail lengths are dynamically regulated during vertebrate embryogenesis at an isoform-specific level, correlating with mRNA decay. Finally, we demonstrate the ability of Nano3P-seq in capturing non-A bases within polyA tails of various lengths, and reveal their distribution during vertebrate embryogenesis. Overall, Nano3P-seq is a simple and robust method for accurately estimating transcript levels, tail lengths, and tail composition heterogeneity in individual reads, with minimal library preparation biases, both in the coding and non-coding transcriptome.

DOI: https://doi.org/10.1038/s41592-022-01714-w
Aging Cell. 2022 Dec 22. e13752

Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts.

Sophia Wedel, Ines Martic, Lena Guerrero Navarro, Christian Ploner, Gerhard Pierer, Pidder Jansen-Dürr, Maria Cavinato.

  Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine also known as a mitokine; however, its role in mitochondrial homeostasis and cellular senescence remained elusive. We show here that knocking down GDF15 expression in human dermal fibroblasts induced mitochondrial dysfunction and premature senescence, associated with a distinct senescence-associated secretory phenotype. Fibroblast-specific loss of GDF15 expression in a model of 3D reconstructed human skin induced epidermal thinning, a hallmark of skin aging. Our results suggest GDF15 to play a so far undisclosed role in mitochondrial homeostasis to delay both the onset of cellular senescence and the appearance of age-related changes in a 3D human skin model.

Keywords:  GDF15; lipofuscin; mitochondria; mitokine; senescence; skin aging

DOI:  https://doi.org/10.1111/acel.13752
Biomolecules. 2022 Nov 28. pii: 1770. [Epub ahead of print]12(12):

The Pathophysiological Significance of "Mitochondrial Ejection" from Cells.

Qintao Fan, Yasuhiro Maejima, Lai Wei, Shun Nakagama, Yuka Shiheido-Watanabe, Tetsuo Sasano.

  Mitochondria have beneficial effects on cells by producing ATP and contributing to various biosynthetic procedures. On the other hand, dysfunctional mitochondria have detrimental effects on cells by inducing cellular damage, inflammation, and causing apoptosis in response to various stimuli. Therefore, a series of mitochondrial quality control pathways are required for the physiological state of cells to be maintained. Recent research has provided solid evidence to support that mitochondria are ejected from cells for transcellular degradation or transferred to other cells as metabolic support or regulatory messengers. In this review, we summarize the current understanding of the regulation of mitochondrial transmigration across the plasma membranes and discuss the functional significance of this unexpected phenomenon, with an additional focus on the impact on the pathogenesis of cardiovascular diseases. We also provide some perspective concerning the unrevealed mechanisms underlying mitochondrial ejection as well as existing problems and challenges concerning the therapeutic application of mitochondrial ejection.

Keywords:  exopher; extracellular vesicles; heart; mitochondria; mitochondrial quality control; mitochondrial transfer; tunneling nanotubes

DOI:  https://doi.org/10.3390/biom12121770
Nucleic Acids Res. 2022 Dec 20. pii: gkac1185. [Epub ahead of print]

Single-read tRNA-seq analysis reveals coordination of tRNA modification and aminoacylation and fragmentation.

Xavier Hernandez-Alias, Christopher D Katanski, Wen Zhang, Mahdi Assari, Christopher P Watkins, Martin H Schaefer, Luis Serrano, Tao Pan.

Transfer RNA (tRNA) utilizes multiple properties of abundance, modification, and aminoacylation in translational regulation. These properties were typically studied one-by-one; however, recent advance in high throughput tRNA sequencing enables their simultaneous assessment in the same sequencing data. How these properties are coordinated at the transcriptome level is an open question. Here, we develop a single-read tRNA analysis pipeline that takes advantage of the pseudo single-molecule nature of tRNA sequencing in NGS libraries. tRNAs are short enough that a single NGS read can represent one tRNA molecule, and can simultaneously report on the status of multiple modifications, aminoacylation, and fragmentation of each molecule. We find correlations among modification-modification, modification-aminoacylation and modification-fragmentation. We identify interdependencies among one of the most common tRNA modifications, m1A58, as coordinators of tissue-specific gene expression. Our method, SingLe-read Analysis of Crosstalks (SLAC), reveals tRNAome-wide networks of modifications, aminoacylation, and fragmentation. We observe changes of these networks under different stresses, and assign a function for tRNA modification in translational regulation and fragment biogenesis. SLAC leverages the richness of the tRNA-seq data and provides new insights on the coordination of tRNA properties.

DOI: https://doi.org/10.1093/nar/gkac1185
Bioessays. 2022 Dec 22. e2200194

The unbroken Krebs cycle. Hormonal-like regulation and mitochondrial signaling to control mitophagy and prevent cell death.

Rafael Franco, Joan Serrano-Marín.

  The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that occur with neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large-scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein-coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal-like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria.

Keywords:  G protein-coupled receptor; Mitochondrial alterations; anaplerotic; glutamate; glutamine; mitophagy; neurodegeneration; signal transduction; signaling in mitochondria; α-ketoglutarate

DOI:  https://doi.org/10.1002/bies.202200194
Am J Pathol. 2022 Dec 16. pii: S0002-9440(22)00397-2. [Epub ahead of print]

Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.

Eun-Jin Lee, Monica Sophia Diaz-Aguilar, Hyejung Min, Jihee Choi, Diego Adrian Valdez Duran, Julia M Grandjean, R Luke Wiseman, Heike Kroeger, Jonathan H Lin.

Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate this question, we analyzed bulk-RNA-seq transcriptomes from retinal-organoids generated from ACHM patients carrying homozygous loss-of-function ATF6 variants. We identified marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids, indicating that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, we compared gene expression from control and ACHM retinal organoids with transcriptome profiles of 7 major retinal cell types generated from recent single-cell transcriptomic maps of non-diseased human retina. Our analysis revealed pronounced down-regulation of cone genes and up-regulation in Müller glia genes, with no significant effects on other retinal cells. Overall, our analysis of ACHM patient retinal organoids identifies new cellular and molecular phenotypes in addition to cone dysfunction: activation of Müller cells, increased ER stress, and disrupted mitochondrial structure and elevated respiratory chain activity gene expression.

DOI: https://doi.org/10.1016/j.ajpath.2022.12.002
Nat Rev Cardiol. 2022 Dec 20.

Single-cell transcriptomics for the assessment of cardiac disease.

Antonio M A Miranda, Vaibhao Janbandhu, Henrike Maatz, Kazumasa Kanemaru, James Cranley, Sarah A Teichmann, Norbert Hübner, Michael D Schneider, Richard P Harvey, Michela Noseda.

Cardiovascular disease is the leading cause of death globally. An advanced understanding of cardiovascular disease mechanisms is required to improve therapeutic strategies and patient risk stratification. State-of-the-art, large-scale, single-cell and single-nucleus transcriptomics facilitate the exploration of the cardiac cellular landscape at an unprecedented level, beyond its descriptive features, and can further our understanding of the mechanisms of disease and guide functional studies. In this Review, we provide an overview of the technical challenges in the experimental design of single-cell and single-nucleus transcriptomics studies, as well as a discussion of the type of inferences that can be made from the data derived from these studies. Furthermore, we describe novel findings derived from transcriptomics studies for each major cardiac cell type in both health and disease, and from development to adulthood. This Review also provides a guide to interpreting the exhaustive list of newly identified cardiac cell types and states, and highlights the consensus and discordances in annotation, indicating an urgent need for standardization. We describe advanced applications such as integration of single-cell data with spatial transcriptomics to map genes and cells on tissue and define cellular microenvironments that regulate homeostasis and disease progression. Finally, we discuss current and future translational and clinical implications of novel transcriptomics approaches, and provide an outlook of how these technologies will change the way we diagnose and treat heart disease.

DOI: https://doi.org/10.1038/s41569-022-00805-7
Mol Biotechnol. 2022 Dec 22.

A Review on Advanced CRISPR-Based Genome-Editing Tools: Base Editing and Prime Editing.

Ali Saber Sichani, Maryam Ranjbar, Maryam Baneshi, Farid Torabi Zadeh, Jafar Fallahi.

  In the field of medicine, it is axiomatic that the need of a precise gene-editing tool is critical to employ therapeutic approaches toward pathogenic mutations, occurring in human genome. Today we know that most of genetic defects are caused by single-base pair substitutions in genomic DNA. The ability to make practically any targeted substitutions of DNA sequences at specified regions in the human genome gives us the chance to employ gene therapy in most known diseases associated with genetic variants. In this regard, CRISPR/Cas9 applications is becoming more and more popular along with the significant advancements of life sciences, by employing this technology in genome-editing and high-throughput screenings. Several CRISPR/Cas-based mammalian cell gene-editing techniques have been developed during the last decade, including nucleases, base editors, and prime editors, all of which have the exact mechanism at first glance. However, they address a subset of known pathogenic sequence mutations using different methods. First, we highlight the development of CRISPR-based gene-editing tools. Then we describe their functions and summarize the conducted research studies, which are increasing the reliability of these strategies to better efficiencies for prospective gene therapies in the near future. Lastly, we compare the capabilities of all these platforms together besides their probable limitations.

Keywords:  Base editing; CRISPR-based tools; CRISPR/Cas9; Gene editing; Prime editing

DOI:  https://doi.org/10.1007/s12033-022-00639-1
Pharmaceutics. 2022 Nov 24. pii: 2588. [Epub ahead of print]14(12):

Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives.

Francesco Bellanti, Aurelio Lo Buglio, Gianluigi Vendemiale.

  An impairment in mitochondrial homeostasis plays a crucial role in the process of aging and contributes to the incidence of age-related diseases, including sarcopenia, which is defined as an age-dependent loss of muscle mass and strength. Mitochondrial dysfunction exerts a negative impact on several cellular activities, including bioenergetics, metabolism, and apoptosis. In sarcopenia, mitochondria homeostasis is disrupted because of reduced oxidative phosphorylation and ATP generation, the enhanced production of reactive species, and impaired antioxidant defense. This review re-establishes the most recent evidence on mitochondrial defects that are thought to be relevant in the pathogenesis of sarcopenia and that may represent promising therapeutic targets for its prevention/treatment. Furthermore, we describe mechanisms of action and translational potential of promising mitochondria-targeted drug delivery systems, including molecules able to boost the metabolism and bioenergetics, counteract apoptosis, antioxidants to scavenge reactive species and decrease oxidative stress, and target mitophagy. Even though these mitochondria-delivered strategies demonstrate to be promising in preclinical models, their use needs to be promoted for clinical studies. Therefore, there is a compelling demand to further understand the mechanisms modulating mitochondrial homeostasis, to characterize powerful compounds that target muscle mitochondria to prevent sarcopenia in aged people.

Keywords:  mitochondrial dysfunction; oxidative stress; sarcopenia

DOI:  https://doi.org/10.3390/pharmaceutics14122588
Nat Biomed Eng. 2022 Dec 23.

Ablating all mitochondrial protein-coding genes.

Xin Lou, Bin Shen.

DOI: https://doi.org/10.1038/s41551-022-00993-0