bims-mitmed 2022-12-25 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–12–25
29 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Moms' mitochondria may refresh cells in sick kids.
Mitochondrial augmentation of hematopoietic stem cells in children with single large-scale mitochondrial DNA deletion syndromes.
Structural functionality of skeletal muscle mitochondria and its correlation with metabolic diseases.
Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases.
Mitochondria Clumping vs. Mitochondria Fusion in CMT2A Diseases.
Mitochondrial Ultrastructural Defects in NDUFS3-Related Disorder.
Chronic progressive external ophthalmoplegia plus syndrome due to Homozygous Missense Variant in TOP3A gene.
Exercise and mitochondrial mechanisms in patients with sarcopenia.
[Leber hereditary optic neuropathy: clinical picture and initial workup data].
Exercise-Boosted Mitochondrial Remodeling in Parkinson's Disease.
The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease.
The Therapeutic Strategies Targeting Mitochondrial Metabolism in Cardiovascular Disease.
Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives.
Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches.
Mitochondria in Early Life.
Adult-onset Leigh Syndrome with a m.9176 T>C Mutation Manifested as Reversible Cerebral Vasoconstriction Syndrome.
Mitochondrial Autophagy in Ischemic Aged Livers.
Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis.
Childhood-Onset Leber Hereditary Optic Neuropathy - Clinical and Prognostic Insights.
Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle.
Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.
Personality traits are consistently associated with blood mitochondrial DNA copy number estimated from genome sequences in two genetic cohort studies.
Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts.
Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity.
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.
Astrocytic mitochondrial frataxin-A promising target for ischemic brain injury.
Elderly onset of MELAS in a male: A case report.
DELE1 is protective for mitochondrial cardiomyopathy.
Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.

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
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 Sci (Lond). 2022 Dec 22. 136(24): 1851-1871

Structural functionality of skeletal muscle mitochondria and its correlation with metabolic diseases.

Gourabamani Swalsingh, Punyadhara Pani, Naresh C Bal.

  The skeletal muscle is one of the largest organs in the mammalian body. Its remarkable ability to swiftly shift its substrate selection allows other organs like the brain to choose their preferred substrate first. Healthy skeletal muscle has a high level of metabolic flexibility, which is reduced in several metabolic diseases, including obesity and Type 2 diabetes (T2D). Skeletal muscle health is highly dependent on optimally functioning mitochondria that exist in a highly integrated network with the sarcoplasmic reticulum and sarcolemma. The three major mitochondrial processes: biogenesis, dynamics, and mitophagy, taken together, determine the quality of the mitochondrial network in the muscle. Since muscle health is primarily dependent on mitochondrial status, the mitochondrial processes are very tightly regulated in the skeletal muscle via transcription factors like peroxisome proliferator-activated receptor-γ coactivator-1α, peroxisome proliferator-activated receptors, estrogen-related receptors, nuclear respiratory factor, and Transcription factor A, mitochondrial. Physiological stimuli that enhance muscle energy expenditure, like cold and exercise, also promote a healthy mitochondrial phenotype and muscle health. In contrast, conditions like metabolic disorders, muscle dystrophies, and aging impair the mitochondrial phenotype, which is associated with poor muscle health. Further, exercise training is known to improve muscle health in aged individuals or during the early stages of metabolic disorders. This might suggest that conditions enhancing mitochondrial health can promote muscle health. Therefore, in this review, we take a critical overview of current knowledge about skeletal muscle mitochondria and the regulation of their quality. Also, we have discussed the molecular derailments that happen during various pathophysiological conditions and whether it is an effect or a cause.

Keywords:  Ca2+-cycling; Type2 Diabetes; exercise; metabolic disorders; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1042/CS20220636
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
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
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
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
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
J Fr Ophtalmol. 2022 Nov;pii: S0181-5512(22)00444-2. [Epub ahead of print]45(8S1): S3-S8

[Leber hereditary optic neuropathy: clinical picture and initial workup data].

C Vignal Clermont.

  Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disease, responsible for blindness by bilateral involvement of central vision. It usually affects young men but can occur at any age and in women. Its diagnosis is suspected on the family history and the initial clinical picture, and the definitive diagnosis of LHON is obtained by genetic testing and the molecular identification of the mitochondrial genetic point mutation. The initial workup should include an assessment of visual structure and function. Its visual prognosis is severe, but depends on the causative mutation. Support should include genetic counseling, a therapeutic proposal and a support for visual impairment.

Keywords:  Leber hereditary optic neuropathy; Maladie mitochondriale; Mitochondrial disease; Nerf optique; Neuropathie optique héréditaire de Leber; Optic nerve; Optical coherence tomography (OCT); Peripapillary telangiectasias; Tomographie en cohérence optique (OCT); Télangiectasies péripapillaires

DOI:  https://doi.org/10.1016/S0181-5512(22)00444-2
Biomedicines. 2022 Dec 12. pii: 3228. [Epub ahead of print]10(12):

Exercise-Boosted Mitochondrial Remodeling in Parkinson's Disease.

Juan Carlos Magaña, Cláudia M Deus, Maria Giné-Garriga, Joel Montané, Susana P Pereira.

  Parkinson's disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons resulting in dopamine deficiency in the striatum. Given the estimated escalation in the number of people with PD in the coming decades, interventions aimed at minimizing morbidity and improving quality of life are crucial. Mitochondrial dysfunction and oxidative stress are intrinsic factors related to PD pathogenesis. Accumulating evidence suggests that patients with PD might benefit from various forms of exercise in diverse ways, from general health improvements to disease-specific effects and, potentially, disease-modifying effects. However, the signaling and mechanism connecting skeletal muscle-increased activity and brain remodeling are poorly elucidated. In this review, we describe skeletal muscle-brain crosstalk in PD, with a special focus on mitochondrial effects, proposing mitochondrial dysfunction as a linker in the muscle-brain axis in this neurodegenerative disease and as a promising therapeutic target. Moreover, we outline how exercise secretome can improve mitochondrial health and impact the nervous system to slow down PD progression. Understanding the regulation of the mitochondrial function by exercise in PD may be beneficial in defining interventions to delay the onset of this neurodegenerative disease.

Keywords:  Parkinson’s disease; exercise; mitochondrial remodeling; muscle–brain communication; non-pharmacological interventions; secretome

DOI:  https://doi.org/10.3390/biomedicines10123228
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
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
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
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
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
Intern Med. 2022 Dec 21.

Adult-onset Leigh Syndrome with a m.9176 T>C Mutation Manifested as Reversible Cerebral Vasoconstriction Syndrome.

Ayane Ohyama-Tamagake, Kimihiko Kaneko, Ryo Itami, Masatsugu Nakano, Yasuhiro Namioka, Rumiko Izumi, Haruka Sato, Hideaki Suzuki, Atsuhito Takeda, Yasushi Okazaki, Yukiko Yatsuka, Takaaki Abe, Kei Murayama, Naoto Sugeno, Tatsuro Misu, Masashi Aoki.

  A 26-year-old woman developed a sudden headache, ptosis, and diplopia. Magnetic resonance imaging and angiography demonstrated a symmetrical lesion from the midbrain to the brainstem, involving the solitary nucleus and multifocal cerebral artery narrowing. Reversible cerebral vasospasm syndrome (RCVS) was suspected, and the patient improved after vasodilatation. Leigh syndrome was suspected due to the elevated serum lactate levels, so mitochondrial DNA was analyzed, and an m.9176 T>C mutation was detected. The final diagnosis was adult-onset Leigh syndrome manifesting as RCVS. An uncontrolled baroreflex due to a solitary nuclear lesion or endothelial dysfunction may have contributed to her unique presentation.

Keywords:  Leigh syndrome; Reversible cerebral vasoconstriction syndrome; mitochondrial disease; thunderclap headache

DOI:  https://doi.org/10.2169/internalmedicine.0773-22
Cells. 2022 Dec 16. pii: 4083. [Epub ahead of print]11(24):

Mitochondrial Autophagy in Ischemic Aged Livers.

Jae-Sung Kim, William C Chapman, Yiing Lin.

  Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.

Keywords:  autophagy; ischemia/reperfusion; liver; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/cells11244083
Diseases. 2022 Dec 01. pii: 117. [Epub ahead of print]10(4):

Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis.

Sayuri Yoshikawa, Kurumi Taniguchi, Haruka Sawamura, Yuka Ikeda, Ai Tsuji, Satoru Matsuda.

  Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, the pathogenesis of which is based on alternations in the mitochondria of motor neurons, causing their progressive death. A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. Mitophagy has been considered one of the main mechanisms responsible for mitochondrial quality control. Since ALS is characterized by enormous oxidative stress, several edible phytochemicals that can activate mitophagy to remove damaged mitochondria could be considered a promising option to treat ALS by providing neuroprotection. Therefore, it is of great significance to explore the mechanisms of mitophagy in ALS and to understand the effects and/or molecular mechanisms of phytochemical action, which could translate into a treatment for neurodegenerative diseases, including ALS.

Keywords:  ALS; AMPK; ROS; mTOR; mTORC1; mitophagy; natural product

DOI:  https://doi.org/10.3390/diseases10040117
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
Int J Mol Sci. 2022 Dec 11. pii: 15707. [Epub ahead of print]23(24):

Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle.

Xueqiao Wang, Zhuying Wei, Mingjuan Gu, Lin Zhu, Chao Hai, Anqi Di, Di Wu, Chunling Bai, Guanghua Su, Xuefei Liu, Lei Yang, Guangpeng Li.

  Myostatin (MSTN) is an important negative regulator of skeletal muscle growth in animals. A lack of MSTN promotes lipolysis and glucose metabolism but inhibits oxidative phosphorylation (OXPHOS). Here, we aimed to investigate the possible mechanism of MSTN regulating the mitochondrial energy homeostasis of skeletal muscle. To this end, MSTN knockout mice were generated by the CRISPR/Cas9 technique. Expectedly, the MSTN null (Mstn-/-) mouse has a hypermuscular phenotype. The muscle metabolism of the Mstn-/- mice was detected by an enzyme-linked immunosorbent assay, indirect calorimetry, ChIP-qPCR, and RT-qPCR. The resting metabolic rate and body temperature of the Mstn-/- mice were significantly reduced. The loss of MSTN not only significantly inhibited the production of ATP by OXPHOS and decreased the activity of respiratory chain complexes, but also inhibited key rate-limiting enzymes related to the TCA cycle and significantly reduced the ratio of NADH/NAD+ in the Mstn-/- mice, which then greatly reduced the total amount of ATP. Further ChIP-qPCR results confirmed that the lack of MSTN inhibited both the TCA cycle and OXPHOS, resulting in decreased ATP production. The reason may be that Smad2/3 is not sufficiently bound to the promoter region of the rate-limiting enzymes Idh2 and Idh3a of the TCA cycle, thus affecting their transcription.

Keywords:  ATP; TCA cycle; energy metabolism; mitochondria; myostatin; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms232415707
Int J Mol Sci. 2022 Dec 12. pii: 15734. [Epub ahead of print]23(24):

Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.

Seo-Eun Lee, Young Cheol Kang, Yujin Kim, Soomin Kim, Shin-Hye Yu, Jong Hyeok Park, In-Hyeon Kim, Hyeon-Young Kim, Kyuboem Han, Hong Kyu Lee, Sung-Hwan Kim, Chun-Hyung Kim.

  Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MTGFP). When MTGFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MTGFP injected intravenously into normal mice, MTGFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.

Keywords:  mitochondria; mitochondrial dysfunction; trafficking; transplantation

DOI:  https://doi.org/10.3390/ijms232415734
Elife. 2022 12 20. pii: e77806. [Epub ahead of print]11

Personality traits are consistently associated with blood mitochondrial DNA copy number estimated from genome sequences in two genetic cohort studies.

Richard F Oppong, Antonio Terracciano, Martin Picard, Yong Qian, Thomas J Butler, Toshiko Tanaka, Ann Zenobia Moore, Eleanor M Simonsick, Krista Opsahl-Ong, Christopher Coletta, Angelina R Sutin, Myriam Gorospe, Susan M Resnick, Francesco Cucca, Sonja W Scholz, Bryan J Traynor, David Schlessinger, Luigi Ferrucci, Jun Ding.

   Background: Mitochondrial DNA copy number (mtDNAcn) in tissues and blood can be altered in conditions like diabetes and major depression and may play a role in aging and longevity. However, little is known about the association between mtDNAcn and personality traits linked to emotional states, metabolic health, and longevity. This study tests the hypothesis that blood mtDNAcn is related to personality traits and mediates the association between personality and mortality.
Methods: We assessed the big five personality domains and facets using the Revised NEO Personality Inventory (NEO-PI-R), assessed depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D), estimated mtDNAcn levels from whole-genome sequencing, and tracked mortality in participants from the Baltimore Longitudinal Study of Aging. Results were replicated in the SardiNIA Project.
Results: We found that mtDNAcn was negatively associated with the Neuroticism domain and its facets and positively associated with facets from the other four domains. The direction and size of the effects were replicated in the SardiNIA cohort and were robust to adjustment for potential confounders in both samples. Consistent with the Neuroticism finding, higher depressive symptoms were associated with lower mtDNAcn. Finally, mtDNAcn mediated the association between personality and mortality risk.
Conclusions: To our knowledge, this is the first study to show a replicable association between mtDNAcn and personality. Furthermore, the results support our hypothesis that mtDNAcn is a biomarker of the biological process that explains part of the association between personality and mortality.
Funding: Support for this work was provided by the Intramural Research Program of the National Institute on Aging (Z01-AG000693, Z01-AG000970, and Z01-AG000949) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. AT was also supported by the National Institute on Aging of the National Institutes of Health Grant R01AG068093.

Keywords:  depressive symptoms; epidemiology; genetics; genome sequence; genomics; global health; human; mitochondrial DNA copy number; mortality risk; personality

DOI:  https://doi.org/10.7554/eLife.77806
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
Nat Metab. 2022 Dec;4(12): 1756-1774

Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity.

Yaling Hu, Kelei Cao, Fang Wang, Weiying Wu, Weihao Mai, Liyao Qiu, Yuxiang Luo, Woo-Ping Ge, Binggui Sun, Ligen Shi, Junming Zhu, Jianmin Zhang, Zhiying Wu, Yicheng Xie, Shumin Duan, Zhihua Gao.

Microglia continuously survey the brain parenchyma and actively shift status following stimulation. These processes demand a unique bioenergetic programme; however, little is known about the metabolic determinants in microglia. By mining large datasets and generating transgenic tools, here we show that hexokinase 2 (HK2), the most active isozyme associated with mitochondrial membrane, is selectively expressed in microglia in the brain. Genetic ablation of HK2 reduced microglial glycolytic flux and energy production, suppressed microglial repopulation, and attenuated microglial surveillance and damage-triggered migration in male mice. HK2 elevation is prominent in immune-challenged or disease-associated microglia. In ischaemic stroke models, however, HK2 deletion promoted neuroinflammation and potentiated cerebral damages. The enhanced inflammatory responses after HK2 ablation in microglia are associated with aberrant mitochondrial function and reactive oxygen species accumulation. Our study demonstrates that HK2 gates both glycolytic flux and mitochondrial activity to shape microglial functions, changes of which contribute to metabolic abnormalities and maladaptive inflammation in brain diseases.

DOI: https://doi.org/10.1038/s42255-022-00707-5
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
CNS Neurosci Ther. 2022 Dec 22.

Astrocytic mitochondrial frataxin-A promising target for ischemic brain injury.

Rimi Hazra, Enrico M Novelli, Xiaoming Hu.

  In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia.

Keywords:  astrocytes; frataxin; ischemia; mitochondria

DOI:  https://doi.org/10.1111/cns.14068
Front Neurol. 2022 ;13 1018529

Elderly onset of MELAS in a male: A case report.

Sheng-Peng Diao, Song-Fa Chen, Ai-Qun Liu, Zhi-Hua Zhou, Zhong-Xing Peng, Ming-Fan Hong.

   Background: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common maternally inherited mitochondrial diseases which rarely affects elderly people.
Case presentation: We reported the case of a 61-year-old male patient with MELAS. He was experiencing acute migraine-like headaches as the first symptoms. Laboratory data showed elevated lactate and creatine kinase levels. Brain magnetic resonance imaging (MRI) found a high signal intensity lesion in the left occipital-temporal-parietal lobe on diffusion-weighted imaging (DWI). Magnetic resonance angiography (MRA) revealed reversible vasoconstriction of the middle cerebral arteries and superficial temporal arteries. A muscle biopsy suggested minor muscle damage. A genetic study revealed a mitochondrial DNA A3243G mutation.
Conclusion: Elderly onset of MELAS is rare and easily misdiagnosed as an ischemic stroke. MELAS with the onset of stroke-like episodes should be considered in adult or elderly patients with imaging findings that are atypical for cerebral infarction. The use of multimodal MRI in the clinical diagnosis of MELAS could be extremely beneficial.

Keywords:  MELAS; magnetic resonance angiography (MRA); magnetic resonance imaging (MRI); migraine; stroke-like episodes

DOI:  https://doi.org/10.3389/fneur.2022.1018529
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
Nature. 2022 Dec 21.

Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.

Victoria Moiseeva, Andrés Cisneros, Valentina Sica, Oleg Deryagin, Yiwei Lai, Sascha Jung, Eva Andrés, Juan An, Jessica Segalés, Laura Ortet, Vera Lukesova, Giacomo Volpe, Alberto Benguria, Ana Dopazo, Salvador Aznar-Benitah, Yasuteru Urano, Antonio Del Sol, Miguel A Esteban, Yasuyuki Ohkawa, Antonio L Serrano, Eusebio Perdiguero, Pura Muñoz-Cánoves.

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

DOI: https://doi.org/10.1038/s41586-022-05535-x