bims-mitmed 2022-03-27 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–03–27
thirty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions.
Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease.
Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module.
Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State.
Peri-operative management of an adult with POLG-related mitochondrial disease.
DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.
Mitochondria Related Cell Death Modalities and Disease.
Thyroid hormone regulates glutamine metabolism and anaplerotic fluxes by inducing mitochondrial glutamate aminotransferase GPT2.
Reviewing the mitochondrial dysfunction paradigm in rodent models as platforms for neuropsychiatric disease research.
Mitochondria transplantation between living cells.
PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem-cell-derived cardiomyocytes.
S-15176 Difumarate Salt Can Impair Mitochondrial Function through Inhibition of the Respiratory Complex III and Permeabilization of the Inner Mitochondrial Membrane.
Extremely Rare Case of Fetal Anemia Due to Mitochondrial Disease Managed with Intrauterine Transfusion.
Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila.
Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.
Recessive cerebellar and afferent ataxias - clinical challenges and future directions.
New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
Oxidative stress facilitates exogenous mitochondria internalization and survival in retinal ganglion precursor-like cells.
Therapeutic targeting of mitophagy in Parkinson's disease.
Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich's Ataxia.
Bioenergetic Aspects of Mitochondrial Actions of Thyroid Hormones.
Prescription Drugs and Mitochondrial Metabolism.
Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.
Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
Targeting proteostasis maintenance and autophagy in senescence.
Nuclear-Mitochondrial Interactions.
Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer's Disease.
Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship.
Transplantation of MITO cells, mitochondria activated cardiac progenitor cells, to the ischemic myocardium of mouse enhances the therapeutic effect.

Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00088-2. [Epub ahead of print]

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.

Marco Rosina, Veronica Ceci, Riccardo Turchi, Li Chuan, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A F de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R Brestoff, Katia Aquilano, Daniele Lettieri-Barbato.

  Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.

Keywords:  adipose tissue; brown adipocytes; extracellular vesicles; homeostasis; immunometabolism; macrophages; mitochondria; mitochondrial quality control; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2022.02.016
Cells. 2022 Mar 12. pii: 974. [Epub ahead of print]11(6):

Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions.

Alessia Nasca, Andrea Legati, Megi Meneri, Melisa Emel Ermert, Chiara Frascarelli, Nadia Zanetti, Manuela Garbellini, Giacomo Pietro Comi, Alessia Catania, Costanza Lamperti, Dario Ronchi, Daniele Ghezzi.

  Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient's muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient's clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient's fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.

Keywords:  ENDOG; endonuclease G; mitochondrial DNA; mitochondrial myopathy; multiple mtDNA deletions

DOI:  https://doi.org/10.3390/cells11060974
HGG Adv. 2022 Apr 14. 3(2): 100097

Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease.

Kyle Thompson, Lucas Bianchi, Francesca Rastelli, Florence Piron-Prunier, Sophie Ayciriex, Claude Besmond, Laurence Hubert, Magalie Barth, Inês A Barbosa, Charu Deshpande, Manali Chitre, Sarju G Mehta, Eric J M Wever, Pascale Marcorelles, Sandra Donkervoort, Dimah Saade, Carsten G Bönnemann, Katherine R Chao, Chunyu Cai, Susan T Iannaccone, Andrew F Dean, Robert McFarland, Frédéric M Vaz, Agnès Delahodde, Robert W Taylor, Agnès Rötig.

  Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.

Keywords:  OXPHOS defect; WES/WGS; cardiolipin; mitochondria; mitochondrial disease; mitochondrial phospholipid

DOI:  https://doi.org/10.1016/j.xhgg.2022.100097
Proc Natl Acad Sci U S A. 2022 Mar 29. 119(13): e2115566119

Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module.

Thomas D Jackson, Jordan J Crameri, Linden Muellner-Wong, Ann E Frazier, Catherine S Palmer, Luke E Formosa, Daniella H Hock, Kenji M Fujihara, Tegan Stait, Alice J Sharpe, David R Thorburn, Michael T Ryan, David A Stroud, Diana Stojanovski.

  SignificanceMitochondria are double-membraned eukaryotic organelles that house the proteins required for generation of ATP, the energy currency of cells. ATP generation within mitochondria is performed by five multisubunit complexes (complexes I to V), the assembly of which is an intricate process. Mutations in subunits of these complexes, or the suite of proteins that help them assemble, lead to a severe multisystem condition called mitochondrial disease. We show that SFXN4, a protein that causes mitochondrial disease when mutated, assists with the assembly of complex I. This finding explains why mutations in SFXN4 cause mitochondrial disease and is surprising because SFXN4 belongs to a family of amino acid transporter proteins, suggesting that it has undergone a dramatic shift in function through evolution.

Keywords:  complex assembly; mitochondria; respiratory chain; sideroflexins

DOI:  https://doi.org/10.1073/pnas.2115566119
Cells. 2022 Mar 19. pii: 1049. [Epub ahead of print]11(6):

Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.

Gerald W Dorn, Xiawei Dang.

  Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich's ataxia, dominant optic atrophy, and Alzheimer's, Huntington's, and Parkinson's diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis.

Keywords:  mitochondrial dynamics; mitofusin; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells11061049
Nat Commun. 2022 Mar 24. 13(1): 1582

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.

Huan Yang, Caroline Sibilla, Raymond Liu, Jina Yun, Bruce A Hay, Craig Blackstone, David C Chan, Robert J Harvey, Ming Guo.

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.

DOI: https://doi.org/10.1038/s41467-022-29071-4
Neurotherapeutics. 2022 Mar 25.

Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State.

Jingwei Lyu, Yuying Zhao, Na Zhang, Xuebi Xu, Rui Zheng, Wenfei Yu, Wang Xin, Chuanzhu Yan, Kunqian Ji.

  Leigh syndrome (LS) is one of the most common mitochondrial encephalopathy diseases in infants. To date, there is still an absence of effective therapy. Bezafibrate (BEZ), a pan-peroxisome proliferator-activated receptor (PPAR) agonist, ameliorates the phenotype of the mouse model of mitochondrial disease via an unclear mechanism. Here, we applied it to Ndufs4 knockout (KO) mice, a widely used LS animal model, to observe the therapeutic effects and metabolic changes associated with BEZ treatment to explore the therapeutic strategies for mitochondrial diseases. Administration of BEZ significantly enhances survival and attenuates disease progression in Ndufs4 KO mice. Decreased oxidative stress and stunted growth were also observed. As a PPAR agonist, we did not find mitochondrial biogenesis or enhanced metabolism upon BEZ treatment. On the contrary, mice with dietary BEZ showed daily torpor bouts and lower metabolic rates. We speculate that activating energy-saving metabolism in mice may be associated with the therapeutic effects of BEZ, but the exact mechanism of action requires further study.

Keywords:  Bezafibrate; Leigh syndrome; Ndufs4 knockout mice; Torpor

DOI:  https://doi.org/10.1007/s13311-022-01216-9
Anaesth Rep. 2022 Jan-Jun;10(1):10(1): e12159

Peri-operative management of an adult with POLG-related mitochondrial disease.

A Valent, L Delorme, E Roland, C Lambe, S Sarnacki, P Cattan, B Plaud.

  POLG-related mitochondrial disease is a rare mitochondrial disorder that is potentially associated with anaesthetic complications such as propofol-related infusion syndrome. A 19-year-old man with mitochondrial DNA deletions and POLG-related disorders presented for an elective robotic Heller-Dor myotomy for the treatment of oesophageal pseudo-achalasia associated with severe gastro-oesophageal reflux. The fasting period was minimised to reduce the risk of metabolic stress. The anaesthetic technique included a rapid sequence induction with propofol and rocuronium, a remifentanil and sevoflurane-based general anaesthesia with multimodal monitoring and peri-operative lactate-free intravenous fluids with added dextrose. The patient did not experience propofol-related infusion syndrome but did have delayed tracheal extubation due to residual neuromuscular blockade requiring a second dose of sugammadex. This report demonstrates the safety of single-use, low-dose propofol in this patient group. Patients with POLG-related mitochondrial disease may be at risk of prolonged neuromuscular blockade, and appropriate dosing of neuromuscular blocking agents with monitoring of neuromuscular blockade is strongly encouraged.

Keywords:  POLG; mitochondrial disease; prolonged NMB risk‐factors; propofol infusion syndrome

DOI:  https://doi.org/10.1002/anr3.12159
Sci Rep. 2022 Mar 23. 12(1): 5031

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.

Layne N Rodden, Kaitlyn M Gilliam, Christina Lam, Teerapat Rojsajjakul, Clementina Mesaros, Chiara Dionisi, Mark Pook, Massimo Pandolfo, David R Lynch, Ian A Blair, Sanjay I Bidichandani.

Epigenetic silencing in Friedreich ataxia (FRDA), induced by an expanded GAA triplet-repeat in intron 1 of the FXN gene, results in deficiency of the mitochondrial protein, frataxin. A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. In a series of FRDA patients, deficiency of frataxin-E protein correlated with the length of the expanded GAA triplet-repeat, and with repeat-induced DNA hypermethylation that occurs in close proximity to the intronic origin of FXN-E. CRISPR-induced epimodification to mimic DNA hypermethylation seen in FRDA reproduced FXN-E transcriptional deficiency. Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency.

DOI: https://doi.org/10.1038/s41598-022-09002-5
Front Cell Dev Biol. 2022 ;10 832356

Mitochondria Related Cell Death Modalities and Disease.

Chuwen Tian, Yifan Liu, Zhuoshu Li, Ping Zhu, Mingyi Zhao.

  Mitochondria are well known as the centre of energy metabolism in eukaryotic cells. However, they can not only generate ATP through the tricarboxylic acid cycle and oxidative phosphorylation but also control the mode of cell death through various mechanisms, especially regulated cell death (RCD), such as apoptosis, mitophagy, NETosis, pyroptosis, necroptosis, entosis, parthanatos, ferroptosis, alkaliptosis, autosis, clockophagy and oxeiptosis. These mitochondria-associated modes of cell death can lead to a variety of diseases. During cell growth, these modes of cell death are programmed, meaning that they can be induced or predicted. Mitochondria-based treatments have been shown to be effective in many trials. Therefore, mitochondria have great potential for the treatment of many diseases. In this review, we discuss how mitochondria are involved in modes of cell death, as well as basic research and the latest clinical progress in related fields. We also detail a variety of organ system diseases related to mitochondria, including nervous system diseases, cardiovascular diseases, digestive system diseases, respiratory diseases, endocrine diseases, urinary system diseases and cancer. We highlight the role that mitochondria play in these diseases and suggest possible therapeutic directions as well as pressing issues that need to be addressed today. Because of the key role of mitochondria in cell death, a comprehensive understanding of mitochondria can help provide more effective strategies for clinical treatment.

Keywords:  ferroptosis; mitochondria; mitochondrial diseases; parthanatos; regulated cell death

DOI:  https://doi.org/10.3389/fcell.2022.832356
Cell Rep. 2022 Mar 22. pii: S2211-1247(22)00306-0. [Epub ahead of print]38(12): 110562

Thyroid hormone regulates glutamine metabolism and anaplerotic fluxes by inducing mitochondrial glutamate aminotransferase GPT2.

Annunziata Gaetana Cicatiello, Serena Sagliocchi, Annarita Nappi, Emery Di Cicco, Caterina Miro, Melania Murolo, Mariano Stornaiuolo, Monica Dentice.

DOI: https://doi.org/10.1016/j.celrep.2022.110562
Mitochondrion. 2022 Mar 17. pii: S1567-7249(22)00021-6. [Epub ahead of print]

Reviewing the mitochondrial dysfunction paradigm in rodent models as platforms for neuropsychiatric disease research.

Daniël van Rensburg, Zander Lindeque, Brian H Harvey, Stephan F Steyn.

  Neuropsychiatric disorders have complex pathophysiological constructs, requiring translational models to improve our understanding thereof. Mitochondrial dysfunction, generally associated with neurodegenerative disorders, is gaining interest as a key factor in the etiology of psychiatric conditions because of the often comorbid psychiatric symptoms observed. Although translational models of psychiatric disorders, supports mitochondrial involvement, these models do not have a dysfunctional bio-energetic system as primary construct. Here, we consider the construct, face, and predictive validity of mitochondrial models from a neuropsychiatric perspective, to identify novel animal models that can improve our understanding of the underlying bio-energetic mechanisms of these conditions and treatments.

Keywords:  Bipolar disorder; Depression; Neurotransmission; Oxidative stress; Schizophrenia; Validity

DOI:  https://doi.org/10.1016/j.mito.2022.03.002
PLoS Biol. 2022 Mar;20(3): e3001576

Mitochondria transplantation between living cells.

Christoph G Gäbelein, Qian Feng, Edin Sarajlic, Tomaso Zambelli, Orane Guillaume-Gentil, Benoît Kornmann, Julia A Vorholt.

Mitochondria and the complex endomembrane system are hallmarks of eukaryotic cells. To date, it has been difficult to manipulate organelle structures within single live cells. We developed a FluidFM-based approach to extract, inject, and transplant organelles from and into living cells with subcellular spatial resolution. The technology combines atomic force microscopy, optical microscopy, and nanofluidics to achieve force and volume control with real-time inspection. We developed dedicated probes that allow minimally invasive entry into cells and optimized fluid flow to extract specific organelles. When extracting single or a defined number of mitochondria, their morphology transforms into a pearls-on-a-string phenotype due to locally applied fluidic forces. We show that the induced transition is calcium independent and results in isolated, intact mitochondria. Upon cell-to-cell transplantation, the transferred mitochondria fuse to the host cells mitochondrial network. Transplantation of healthy and drug-impaired mitochondria into primary keratinocytes allowed monitoring of mitochondrial subpopulation rescue. Fusion with the mitochondrial network of recipient cells occurred 20 minutes after transplantation and continued for over 16 hours. After transfer of mitochondria and cell propagation over generations, donor mitochondrial DNA (mtDNA) was replicated in recipient cells without the need for selection pressure. The approach opens new prospects for the study of organelle physiology and homeostasis, but also for therapy, mechanobiology, and synthetic biology.

DOI: https://doi.org/10.1371/journal.pbio.3001576
Cell Stem Cell. 2022 Mar 22. pii: S1934-5909(22)00097-2. [Epub ahead of print]

PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem-cell-derived cardiomyocytes.

Nadeera M Wickramasinghe, David Sachs, Bhavana Shewale, David M Gonzalez, Priyanka Dhanan-Krishnan, Denis Torre, Elizabeth LaMarca, Serena Raimo, Rafael Dariolli, Madhavika N Serasinghe, Joshua Mayourian, Robert Sebra, Kristin Beaumont, Srinivas Iyengar, Deborah L French, Arne Hansen, Thomas Eschenhagen, Jerry E Chipuk, Eric A Sobie, Adam Jacobs, Schahram Akbarian, Harry Ischiropoulos, Avi Ma'ayan, Sander M Houten, Kevin Costa, Nicole C Dubois.

  Pluripotent stem-cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease, but they are functionally and structurally immature. Here, we induce efficient human PSC-CM (hPSC-CM) maturation through metabolic-pathway modulations. Specifically, we find that peroxisome-proliferator-associated receptor (PPAR) signaling regulates glycolysis and fatty acid oxidation (FAO) in an isoform-specific manner. While PPARalpha (PPARa) is the most active isoform in hPSC-CMs, PPARdelta (PPARd) activation efficiently upregulates the gene regulatory networks underlying FAO, increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation, and augments FAO flux. PPARd activation further increases binucleation, enhances myofibril organization, and improves contractility. Transient lactate exposure, which is frequently used for hPSC-CM purification, induces an independent cardiac maturation program but, when combined with PPARd activation, still enhances oxidative metabolism. In summary, we investigate multiple metabolic modifications in hPSC-CMs and identify a role for PPARd signaling in inducing the metabolic switch from glycolysis to FAO in hPSC-CMs.

Keywords:  PPAR signaling; cardiac maturation; fatty acid oxidation; metabolism; stem cells

DOI:  https://doi.org/10.1016/j.stem.2022.02.011
Biology (Basel). 2022 Feb 27. pii: 380. [Epub ahead of print]11(3):

S-15176 Difumarate Salt Can Impair Mitochondrial Function through Inhibition of the Respiratory Complex III and Permeabilization of the Inner Mitochondrial Membrane.

Natalia V Belosludtseva, Vlada S Starinets, Alena A Semenova, Anastasia D Igoshkina, Mikhail V Dubinin, Konstantin N Belosludtsev.

  S-15176 difumarate salt, a derivative of the anti-ischemic metabolic drug trimetazidine, has been intensively studied for its impact on cellular metabolism in animal models of ischemia-reperfusion injury of the liver, heart, spinal cord, and other organs. Despite evidence of some reduction in oxidative damage to cells, the results of therapy with S-15176 have been mostly disappointing, possibly because of the lack of data on its underlying mechanisms. Here, we aimed to investigate in more detail the role of complexes I-IV of the electron transport chain and membrane permeability transition in mitochondrial toxicity associated with S-15176. Using rat thymocyte and liver mitochondria, we demonstrated that: (1) acute exposure to S-15176 (10 to 50 μM) dose-dependently decreased the mitochondrial membrane potential; (2) S-15176 suppressed the ADP-stimulated (State 3) and uncoupled (State 3UDNP) respiration of mitochondria energized with succinate or malate/glutamate, but not ascorbate/TMPD, and increased the resting respiration (State 4) when using all the substrate combinations; (3) S-15176 directly inhibited the activity of the respiratory complex III; (4) low doses of S-15176 diminished the rate of H2O2 production by mitochondria; (5) at concentrations of above 30 μM, S-15176 reduced calcium retention capacity and contributed to mitochondrial membrane permeabilization. Taken together, these findings suggest that S-15176 at tissue concentrations reached in animals can impair mitochondrial function through suppression of the cytochrome bc1 complex and an increase in the nonspecific membrane permeability.

Keywords:  S-15176; electron transport chain; mitochondria; mitochondrial membrane permeabilization; mitochondrial membrane potential; mitochondrial respiration

DOI:  https://doi.org/10.3390/biology11030380
Medicina (Kaunas). 2022 Feb 22. pii: 328. [Epub ahead of print]58(3):

Extremely Rare Case of Fetal Anemia Due to Mitochondrial Disease Managed with Intrauterine Transfusion.

Jinha Chung, Mi-Young Lee, Jin-Hoon Chung, Hye-Sung Won.

  This report describes a rare case of fetal anemia, confirmed as a mitochondrial disease after birth, treated with intrauterine transfusion (IUT). Although mitochondrial diseases have been described in newborns, research on their prenatal features is lacking. A patient was referred to our institution at 32 gestational weeks owing to fetal hydrops. Fetal anemia was confirmed by cordocentesis. After IUT had been performed three times, the anemia and associated fetal hydrops showed improvement. However, after birth, the neonate had recurrent pancytopenia and lactic acidosis. He was eventually diagnosed with Pearson syndrome and died 2 months after birth. This is the first case report of fetal anemia associated with mitochondrial disease managed with IUT.

Keywords:  Pearson syndrome; anemia; blood transfusion; case report; hydrops fetalis; mitochondrial diseases

DOI:  https://doi.org/10.3390/medicina58030328
EMBO J. 2022 Mar 23. e109049

Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila.

Shamsi Emtenani, Elliot T Martin, Attila Gyoergy, Julia Bicher, Jakob-Wendelin Genger, Thomas Köcher, Maria Akhmanova, Mariana Guarda, Marko Roblek, Andreas Bergthaler, Thomas R Hurd, Prashanth Rangan, Daria E Siekhaus.

  Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysine-α-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors.

Keywords:  immune cell infiltration; mitochondrial bioenergetics; oxidative phosphorylation; protein translation; transcription factor

DOI:  https://doi.org/10.15252/embj.2021109049
Sci Rep. 2022 Mar 25. 12(1): 5196

Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice.

Gregory S McElroy, Ram P Chakrabarty, Karis B D'Alessandro, Karthik Vasan, Jerica Tan, Joshua S Stoolman, Samuel E Weinberg, Elizabeth M Steinert, Paul A Reyfman, Benjamin D Singer, Warren C Ladiges, Lin Gao, José Lopéz-Barneo, G R Scott Budinger, Navdeep S Chandel.

Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson's disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/-) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.

DOI: https://doi.org/10.1038/s41598-022-09074-3
Nat Rev Neurol. 2022 Mar 24.

Recessive cerebellar and afferent ataxias - clinical challenges and future directions.

Marie Beaudin, Mario Manto, Jeremy D Schmahmann, Massimo Pandolfo, Nicolas Dupre.

Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement. In this Review, we discuss the typical and atypical phenotypes of Friedreich ataxia and CANVAS, along with the features of other recessive ataxias that present with a ganglionopathy or polyneuropathy, with an emphasis on recently described clinical features, natural history and genotype-phenotype correlations. We review the main developments in understanding the complex pathology that affects the sensory neurons and cerebellum, which seem to be most vulnerable to disorders that affect mitochondrial function and DNA repair mechanisms. Finally, we discuss disease-modifying therapeutic advances in Friedreich ataxia, highlighting the most promising candidate molecules and lessons learned from previous clinical trials.

DOI: https://doi.org/10.1038/s41582-022-00634-9
Brain Commun. 2022 ;4(2): fcac030

New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).

Marc Corral-Juan, Pilar Casquero, Natalia Giraldo-Restrepo, Steve Laurie, Alicia Martinez-Piñeiro, Raidili Cristina Mateo-Montero, Lourdes Ispierto, Dolores Vilas, Eduardo Tolosa, Victor Volpini, Ramiro Alvarez-Ramo, Ivelisse Sánchez, Antoni Matilla-Dueñas.

  Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z max = 3.43; θ = 0.00; P < 3.53 × 10-5). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions.

Keywords:  SAMD9L; SCA49; mitochondria; spinocerebellar ataxia; zebrafish

DOI:  https://doi.org/10.1093/braincomms/fcac030
Sci Rep. 2022 Mar 24. 12(1): 5122

Oxidative stress facilitates exogenous mitochondria internalization and survival in retinal ganglion precursor-like cells.

Michal Aharoni-Simon, Keren Ben-Yaakov, Maya Sharvit-Bader, Daniel Raz, Yasmin Haim, Waleed Ghannam, Noga Porat, Hana Leiba, Arie Marcovich, Avital Eisenberg-Lerner, Ziv Rotfogel.

Ocular cells are highly dependent on mitochondrial function due to their high demand of energy supply and their constant exposure to oxidative stress. Indeed, mitochondrial dysfunction is highly implicated in various acute, chronic, and genetic disorders of the visual system. It has recently been shown that mitochondrial transplantation (MitoPlant) temporarily protects retinal ganglion cells (RGCs) from cell death during ocular ischemia. Here, we characterized MitoPlant dynamics in retinal ganglion precursor-like cells, in steady state and under oxidative stress. We developed a new method for detection of transplanted mitochondria using qPCR, based on a difference in the mtDNA sequence of C57BL/6 and BALB/c mouse strains. Using this approach, we show internalization of exogenous mitochondria already three hours after transplantation, and a decline in mitochondrial content after twenty four hours. Interestingly, exposure of target cells to moderate oxidative stress prior to MitoPlant dramatically enhanced mitochondrial uptake and extended the survival of mitochondria in recipient cells by more than three fold. Understanding the factors that regulate the exogenous mitochondrial uptake and their survival may promote the application of MitoPlant for treatment of chronic and genetic mitochondrial diseases.

DOI: https://doi.org/10.1038/s41598-022-08747-3
Biochem Soc Trans. 2022 Mar 21. pii: BST20211107. [Epub ahead of print]

Therapeutic targeting of mitophagy in Parkinson's disease.

Shashank Masaldan, Sylvie Callegari, Grant Dewson.

  Parkinson's disease is a neurodegenerative disorder characterised by cardinal motor symptoms and a diverse range of non-motor disorders in patients. Parkinson's disease is the fastest growing neurodegenerative condition and was described for the first time over 200 years ago, yet there are still no reliable diagnostic markers and there are only treatments that temporarily alleviate symptoms in patients. Early-onset Parkinson's disease is often linked to defects in specific genes, including PINK1 and Parkin, that encode proteins involved in mitophagy, the process of selective autophagic elimination of damaged mitochondria. Impaired mitophagy has been associated with sporadic Parkinson's and agents that damage mitochondria are known to induce Parkinson's-like motor symptoms in humans and animal models. Thus, modulating mitophagy pathways may be an avenue to treat a subset of early-onset Parkinson's disease that may additionally provide therapeutic opportunities in sporadic disease. The PINK1/Parkin mitophagy pathway, as well as alternative mitophagy pathways controlled by BNIP3L/Nix and FUNDC1, are emerging targets to enhance mitophagy to treat Parkinson's disease. In this review, we report the current state of the art of mitophagy-targeted therapeutics and discuss the approaches being used to overcome existing limitations to develop innovative new therapies for Parkinson's disease. Key approaches include the use of engineered mouse models that harbour pathogenic mutations, which will aid in the preclinical development of agents that can modulate mitophagy. Furthermore, the recent development of chimeric molecules (AUTACs) that can bypass mitophagy pathways to eliminate damaged mitochondria thorough selective autophagy offer new opportunities.

Keywords:  PTEN induced putative kinase 1; Parkin; Parkinsons disease; mitochondria; mitophagy; ubiquitin

DOI:  https://doi.org/10.1042/BST20211107
Front Neurosci. 2022 ;16 838335

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich's Ataxia.

Beata Monfort, Kristian Want, Sylvain Gervason, Benoit D'Autréaux.

  Friedreich's ataxia (FRDA) is the most prevalent autosomic recessive ataxia and is associated with a severe cardiac hypertrophy and less frequently diabetes. It is caused by mutations in the gene encoding frataxin (FXN), a small mitochondrial protein. The primary consequence is a defective expression of FXN, with basal protein levels decreased by 70-98%, which foremost affects the cerebellum, dorsal root ganglia, heart and liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, iron accumulation and deposition in mitochondria, and sensitivity to oxidative stress. Based on these phenotypes and the proposed ability of FXN to bind iron, a role as an iron storage protein providing iron for Fe-S cluster and heme biosynthesis was initially proposed. However, this model was challenged by several other studies and it is now widely accepted that FXN functions primarily in Fe-S cluster biosynthesis, with iron accumulation, heme deficiency and oxidative stress sensitivity appearing later on as secondary defects. Nonetheless, the biochemical function of FXN in Fe-S cluster biosynthesis is still debated. Several roles have been proposed for FXN: iron chaperone, gate-keeper of detrimental Fe-S cluster biosynthesis, sulfide production stimulator and sulfur transfer accelerator. A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.

Keywords:  Friedreich’s ataxia; frataxin; iron-sulfur cluster; persulfide; therapy

DOI:  https://doi.org/10.3389/fnins.2022.838335
Cells. 2022 Mar 15. pii: 997. [Epub ahead of print]11(6):

Bioenergetic Aspects of Mitochondrial Actions of Thyroid Hormones.

Federica Cioffi, Antonia Giacco, Fernando Goglia, Elena Silvestri.

  Much is known, but there is also much more to discover, about the actions that thyroid hormones (TH) exert on metabolism. Indeed, despite the fact that thyroid hormones are recognized as one of the most important regulators of metabolic rate, much remains to be clarified on which mechanisms control/regulate these actions. Given their actions on energy metabolism and that mitochondria are the main cellular site where metabolic transformations take place, these organelles have been the subject of extensive investigations. In relatively recent times, new knowledge concerning both thyroid hormones (such as the mechanisms of action, the existence of metabolically active TH derivatives) and the mechanisms of energy transduction such as (among others) dynamics, respiratory chain organization in supercomplexes and cristes organization, have opened new pathways of investigation in the field of the control of energy metabolism and of the mechanisms of action of TH at cellular level. In this review, we highlight the knowledge and approaches about the complex relationship between TH, including some of their derivatives, and the mitochondrial respiratory chain.

Keywords:  bioenergetics; iodothyronines; mitochondrial proteomics

DOI:  https://doi.org/10.3390/cells11060997
Biosci Rep. 2022 Mar 22. pii: BSR20211813. [Epub ahead of print]

Prescription Drugs and Mitochondrial Metabolism.

Cameron Alan Schmidt.

  Mitochondria are central to the physiology and survival of nearly all eukaryotic cells and house diverse metabolic processes including oxidative phosphorylation, reactive oxygen species buffering, metabolite synthesis/exchange, and Ca2+ sequestration. Mitochondria are phenotypically heterogeneous and this variation is essential to the complexity of physiological function among cells, tissues, and organ systems. As a consequence of mitochondrial integration with so many physiological processes, small molecules that modulate mitochondrial metabolism induce complex systemic effects. In the case of many common prescribed drugs, these interactions may contribute to drug therapeutic mechanisms, induce adverse drug reactions, or both. The purpose of this article is to review historical and recent advances in the understanding of the effects of prescription drugs on mitochondrial metabolism. Specific 'modes' of xenobiotic-mitochondria interactions are discussed to provide a set of qualitative models that aid in conceptualizing how the mitochondrial energy transduction system may be affected. Findings of recent in vitro high-throughput screening studies are reviewed, and a few candidate drug classes are chosen for additional brief discussion (i.e. antihyperglycemics, antidepressants, antibiotics, and antihyperlipidemics). Finally, recent improvements in pharmacokinetic models that aid in quantifying systemic effects of drug-mitochondria interactions are briefly considered.

Keywords:  Metabolism; Pharmacology; Prescription Drugs; Xenobiotics; mitochondria

DOI:  https://doi.org/10.1042/BSR20211813
Front Aging Neurosci. 2022 ;14 785761

Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.

Li Gao, Fan Liu, Pin-Pin Hou, Anatol Manaenko, Zhi-Peng Xiao, Fei Wang, Tian-Le Xu, Qin Hu.

  Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H2O2), N-methyl-D-aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a "help-me" signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.

Keywords:  ischemic stroke; metabolic stress; mitochondrial biogenesis; mitochondrial release; neuron-glial crosstalk

DOI:  https://doi.org/10.3389/fnagi.2022.785761
iScience. 2022 Apr 15. 25(4): 103996

Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.

Tatsuya Yamada, Daisuke Murata, David E Kleiner, Robert Anders, Avi Z Rosenberg, Jeffrey Kaplan, James P Hamilton, Mariam Aghajan, Moshe Levi, Nae-Yuh Wang, Ted M Dawson, Toru Yanagawa, Andrew F Powers, Miho Iijima, Hiromi Sesaki.

  Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in patients with NASH. It has been shown that gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet. However, it is unknown whether blocking mitochondrial fusion mitigates NASH pathologies. Here, we acutely depleted OPA1 using antisense oligonucleotides in the NASH mouse model before or after megamitochondria formation. When OPA1 ASOs were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the MCD model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease.

Keywords:  Cell biology; Hepatology

DOI:  https://doi.org/10.1016/j.isci.2022.103996
Aging (Albany NY). 2022 Mar 07. 14(5): 2016-2017

Targeting proteostasis maintenance and autophagy in senescence.

Valentin L'Hôte, Carl Mann, Jean-Yves Thuret.



Keywords:  BRAF-V600E; cellular senescence; proteostasis; selective autophagy; senolytics

DOI:  https://doi.org/10.18632/aging.203941
Biomolecules. 2022 Mar 10. pii: 427. [Epub ahead of print]12(3):

Nuclear-Mitochondrial Interactions.

Brittni R Walker, Carlos T Moraes.

  Mitochondria, the cell's major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship.

Keywords:  MAMs; integrated stress response; mitochondria; nucleus; retrograde signaling

DOI:  https://doi.org/10.3390/biom12030427
Antioxidants (Basel). 2022 Mar 08. pii: 515. [Epub ahead of print]11(3):

Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer's Disease.

Francisca Villavicencio-Tejo, Margrethe A Olesen, Alejandra Aránguiz, Rodrigo A Quintanilla.

  Alzheimer's disease (AD) is characterized by memory and cognitive impairment, accompanied by the accumulation of extracellular deposits of amyloid β-peptide (Aβ) and the presence of neurofibrillary tangles (NFTs) composed of pathological forms of tau protein. Mitochondrial dysfunction and oxidative stress are also critical elements for AD development. We previously showed that the presence of caspase-3 cleaved tau, a relevant pathological form of tau in AD, induced mitochondrial dysfunction and oxidative damage in different neuronal models. Recent studies demonstrated that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a significant role in the antioxidant response promoting neuroprotection. Here, we studied the effects of Nrf2 activation using sulforaphane (SFN) against mitochondrial injury induced by caspase-3 cleaved tau. We used immortalized cortical neurons to evaluate mitochondrial bioenergetics and ROS levels in control and SFN-treated cells. Expression of caspase-3 cleaved tau induced mitochondrial fragmentation, depolarization, ATP loss, and increased ROS levels. Treatment with SFN for 24 h significantly prevented these mitochondrial abnormalities, and reduced ROS levels. Analysis of Western blots and rt-PCR studies showed that SFN treatment increased the expression of several Nrf2-related antioxidants genes in caspase-3 cleaved tau cells. These results indicate a potential role of the Nrf2 pathway in preventing mitochondrial dysfunction induced by pathological forms of tau in AD.

Keywords:  Alzheimer’s disease; Nrf2; antioxidant; mitochondrial dysfunction; neuroprotection; sulforaphane; tau

DOI:  https://doi.org/10.3390/antiox11030515
Metabolites. 2022 Mar 09. pii: 233. [Epub ahead of print]12(3):

Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship.

Niccolò Candelise, Illari Salvatori, Silvia Scaricamazza, Valentina Nesci, Henri Zenuni, Alberto Ferri, Cristiana Valle.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu-Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial "metabolic threshold", which may appear pivotal in ALS pathogenesis.

Keywords:  amyotrophic lateral sclerosis; bioenergetic; metabolism; mitochondria; motor neuron disease

DOI:  https://doi.org/10.3390/metabo12030233
Sci Rep. 2022 Mar 22. 12(1): 4344

Transplantation of MITO cells, mitochondria activated cardiac progenitor cells, to the ischemic myocardium of mouse enhances the therapeutic effect.

Daisuke Sasaki, Jiro Abe, Atsuhito Takeda, Hideyoshi Harashima, Yuma Yamada.

Given the potential for myocardial stem cell transplantation as a promising treatment for heart failure, numerous clinical trials have been conducted and its usefulness has been clearly confirmed. However, the low rate of engraftment of transplanted cells has become a clinical problem, and this needs to be improved in the case of transplanting cells to the heart. To address this issue, we report on attempts to prepare mitochondria-activated stem cells (MITO cells) for use in transplantation. MITO cells, which is cardiac progenitor cells (CPCs) activated by the mitochondrial delivery of resveratrol with an anti-oxidant and mitochondrial activation effects were successfully prepared using a mitochondrial targeting nanocarrier (MITO-Porter). The purpose of this study was to validate the therapeutic effect of cell transplantation by the MITO cells using a mouse model of myocardial ischemia-reperfusion. Mouse CPCs were used as transplanted cells. The transplantation of CPCs and MITO cells were conducted after myocardial ischemia-reperfusion, and the therapeutic effect was determined. The MITO cells transplanted group showed increase in postoperative weight gain, improve cardiac function and inhibition of fibrosis compared to the non-transplanted group and the CPC group. The transplantation of MITO cells to the ischemic myocardium showed a stronger transplantation effect compared to conventional CPC transplantation.

DOI: https://doi.org/10.1038/s41598-022-08583-5