bims-mitmed 2022-04-10 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–04–10
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

DELE1 tracks perturbed protein import and processing in human mitochondria.
CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA.
Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene.
FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.
Genetic, biochemical and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after introduction of newborn screening in the Netherlands.
Impairment of mitochondrial respiration in platelets and placentas: a pilot study in preeclamptic pregnancies.
Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases.
Activated glia cells cause bioenergetic impairment of neurons that can be rescued by knock-down of the mitochondrial calcium uniporter.
Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases.
Mitochondrial transfer in BAT.
Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns.
Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.
A novel anticancer pharmacological agent targeting mitochondrial complex I.
Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.
Mitochondrial Population in Mouse Eosinophils: Ultrastructural Dynamics in Cell Differentiation and Inflammatory Diseases.
Genetic disorders of cellular trafficking.
MitoScore, MitoGrade, or MitoSure: what does embryonic mitochondrial deoxyribonucleic acid quantification actually measure and is it useful?
Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.
Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy.
Mitochondrial Mass of Naïve T Cells Is Associated with Aerobic Fitness and Energy Expenditure of Active and Inactive Adults.
Dietary restriction modulates mitochondrial DNA damage and oxylipins profile in aged rats.
Mitochondria as Mediators of Systemic Inflammation and Organ Cross-talk in Acute Kidney Injury.

Nat Commun. 2022 Apr 06. 13(1): 1853

DELE1 tracks perturbed protein import and processing in human mitochondria.

Evelyn Fessler, Luisa Krumwiede, Lucas T Jae.

Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.

DOI: https://doi.org/10.1038/s41467-022-29479-y
Nat Biotechnol. 2022 Apr 04.

CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA.

Beverly Y Mok, Anna V Kotrys, Aditya Raguram, Tony P Huang, Vamsi K Mootha, David R Liu.

The all-protein cytosine base editor DdCBE uses TALE proteins and a double-stranded DNA-specific cytidine deaminase (DddA) to mediate targeted C•G-to-T•A editing. To improve editing efficiency and overcome the strict TC sequence-context constraint of DddA, we used phage-assisted non-continuous and continuous evolution to evolve DddA variants with improved activity and expanded targeting scope. Compared to canonical DdCBEs, base editors with evolved DddA6 improved mitochondrial DNA (mtDNA) editing efficiencies at TC by 3.3-fold on average. DdCBEs containing evolved DddA11 offered a broadened HC (H = A, C or T) sequence compatibility for both mitochondrial and nuclear base editing, increasing average editing efficiencies at AC and CC targets from less than 10% for canonical DdCBE to 15-30% and up to 50% in cell populations sorted to express both halves of DdCBE. We used these evolved DdCBEs to efficiently install disease-associated mtDNA mutations in human cells at non-TC target sites. DddA6 and DddA11 substantially increase the effectiveness and applicability of all-protein base editing.

DOI: https://doi.org/10.1038/s41587-022-01256-8
Gene Ther. 2022 Apr 06.

Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene.

Yuan Liu, Jeremy D Eastwood, Diego E Alba, Sindhu Velmurugan, Ning Sun, Vittorio Porciatti, Richard K Lee, William W Hauswirth, John Guy, Hong Yu.

Therapies for genetic disorders caused by mutated mitochondrial DNA are an unmet need, in large part due barriers in delivering DNA to the organelle and the absence of relevant animal models. We injected into mouse eyes a mitochondrially targeted Adeno-Associated-Virus (MTS-AAV) to deliver the mutant human NADH ubiquinone oxidoreductase subunit I (hND1/m.3460 G > A) responsible for Leber's hereditary optic neuropathy, the most common primary mitochondrial genetic disease. We show that the expression of the mutant hND1 delivered to retinal ganglion cells (RGC) layer colocalizes with the mitochondrial marker PORIN and the assembly of the expressed hND1 protein into host respiration complex I. The hND1-injected eyes exhibit hallmarks of the human disease with progressive loss of RGC function and number, as well as optic nerve degeneration. We also show that gene therapy in the hND1 eyes by means of an injection of a second MTS-AAV vector carrying wild-type human ND1 restores mitochondrial respiratory complex I activity, the rate of ATP synthesis and protects RGCs and their axons from dysfunction and degeneration. These results prove that MTS-AAV is a highly efficient gene delivery approach with the ability to create mito-animal models and has the therapeutic potential to treat mitochondrial genetic diseases.

DOI: https://doi.org/10.1038/s41434-022-00333-6
Sci Adv. 2022 Apr 08. 8(14): eabn7105

FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction.

Marijana Croon, Karolina Szczepanowska, Milica Popovic, Christina Lienkamp, Katharina Senft, Christoph Paul Brandscheid, Theresa Bock, Leoni Gnatzy-Feik, Artem Ashurov, Richard James Acton, Harshita Kaul, Claire Pujol, Stephan Rosenkranz, Marcus Krüger, Aleksandra Trifunovic.

The mitochondrial integrated stress response (mitoISR) has emerged as a major adaptive pathway to respiratory chain deficiency, but both the tissue specificity of its regulation, and how mitoISR adapts to different levels of mitochondrial dysfunction are largely unknown. Here, we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration, and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue specificity and dose dependency of mitoISR.

DOI: https://doi.org/10.1126/sciadv.abn7105
J Inherit Metab Dis. 2022 Apr 05.

Genetic, biochemical and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after introduction of newborn screening in the Netherlands.

Marit Schwantje, Sabine A Fuchs, Lonneke de Boer, Annet M Bosch, Inge Cuppen, Eugenie Dekkers, Terry G J Derks, Sacha Ferdinandusse, Lodewijk IJlst, Riekelt H Houtkooper, Rose Maase, W Ludo van der Pol, Maaike C de Vries, Rendelien K Verschoof-Puite, Ronald J A Wanders, Monique Williams, Frits Wijburg, Gepke Visser.

INTRODUCTION: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but all different deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid β-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH), and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD).
AIM: To gain insight in the outcomes of MTP-deficient patients diagnosed after introduction of NBS for LCHADD in the Netherlands.
METHODS: Retrospective evaluation of genetic, biochemical and clinical characteristics of MTP-deficient patients, identified since 2007.
RESULTS: Thirteen patients were identified: seven with LCHADD, five with MTPD and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within one month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy.
CONCLUSION: Patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.

DOI: https://doi.org/10.1002/jimd.12502
Mol Cell Biochem. 2022 Apr 07.

Impairment of mitochondrial respiration in platelets and placentas: a pilot study in preeclamptic pregnancies.

Anca M Bînă, Oana M Aburel, Vlad F Avram, Theia Lelcu, Adina V Lința, Daniela V Chiriac, Adelina G Mocanu, Elena Bernad, Claudia Borza, Marius L Craina, Zoran L Popa, Danina M Muntean, Octavian M Crețu.

  Preeclampsia (PE) is a major complication of pregnancy with partially elucidated pathophysiology. Placental mitochondrial dysfunction has been increasingly studied as major pathomechanism in both early- and late-onset PE. Impairment of mitochondrial respiration in platelets has recently emerged as a peripheral biomarker that may mirror organ mitochondrial dysfunction in several acute and chronic pathologies. The present study was purported to assess mitochondrial respiratory dys/function in both platelets and placental mitochondria in PE pregnancies. To this aim, a high-resolution respirometry SUIT (Substrate-Uncoupler-Inhibitor-Titration) protocol was adapted to assess complex I (glutamate + malate)- and complex II (succinate)-supported respiration. A decrease in all respiratory parameters (basal, coupled, and maximal uncoupled respiration) in peripheral platelets was found in preeclamptic as compared to healthy pregnancies. At variance, placental mitochondria showed a dichotomous behavior in preeclampsia in relation to the fetal birth weight. PE pregnancies with fetal growth restriction were associated with decreased in coupled respiration (oxidative phosphorylation/OXPHOS capacity) and maximal uncoupled respiration (electron transfer/ET capacity). At variance, these respiratory parameters were increased for both complex I- and II-supported respiration in PE pregnancies with normal weight fetuses. Large randomized controlled clinical studies are needed in order to advance our understanding of mitochondrial adaptive vs. pathological changes in preeclampsia.

Keywords:  Fetal growth restriction; High-resolution respirometry; Mitochondria; Placenta; Platelet; Preeclampsia

DOI:  https://doi.org/10.1007/s11010-022-04415-2
Mol Genet Genomic Med. 2022 Apr 07. e1943

Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases.

Chong Sun, Shengyang Wu, Ruiguo Chen, Junwu Liu, Jiasen Wang, Yanyun Ma, Zhulin Yuan, Yuezhen Li.

   BACKGROUND: Mitochondrial disease (MD) is genetically a heterogeneous group of disorders with impairment in respiratory chain complexes or pathways associated with the mitochondrial function. Nowadays, it is still a challenge for the genetic screening of MD due to heteroplasmy of mitochondrial genome and the complex model of inheritance. This study was designed to investigate the feasibility of whole exome sequencing (WES)-based testing as an alternative option for the diagnosis of MD.
METHODS: A Chinese Han cohort of 48 patients with suspect MD features was tested using nanoWES, which was a self-designed WES technique that covered the complete mtDNA genome and 21,019 nuclear genes. Fourteen patients were identified with a single genetic variant and three with single deletion in mtDNA.
RESULTS: The heteroplasmy levels of variants in mitochondrial genome range from 11% to 100%. NanoWES failed to identify multiple deletions in mtDNA compared with long range PCR and massively parallel sequencing (LR-PCR/MPS). However, our testing showed obvious advantages in identifying variations in nuclear DNA. Based on nanoWES, we identified two patients with nuclear DNA variation. One of them showed Xp22.33-q28 duplication, which indicated a possibility of Klinefelter syndrome.
CONCLUSION: NanoWES yielded a diagnostic rate of 35.4% for MD. With the rapid advances of next generation sequencing technique and decrease in cost, we recommend the usage of nanoWES as a first-line method in clinical diagnosis.

Keywords:  genetic diagnosis; mitochondrial disease; next generation sequencing; whole exome sequencing

DOI:  https://doi.org/10.1002/mgg3.1943
Biochem Biophys Res Commun. 2022 Mar 25. pii: S0006-291X(22)00465-X. [Epub ahead of print]608 45-51

Activated glia cells cause bioenergetic impairment of neurons that can be rescued by knock-down of the mitochondrial calcium uniporter.

Angela Maria Casaril, Athanasios Katsalifis, Rolf M Schmidt, Carlos Bas-Orth.

  Neuroinflammation is a hallmark of various neurological disorders including autoimmune-, neurodegenerative and neuropsychiatric diseases. In neuroinflammation, activated microglia and astrocytes release soluble mediators such as cytokines, glutamate, and reactive oxygen species that negatively affect neuronal function and viability, and thus contribute to neurodegeneration during disease progression. Therefore, the development of neuroprotective strategies might be important in addition to treating inflammation in these diseases. Mitochondria are promising cellular targets for neuroprotective interventions: They are among the first structures affected in many neuroinflammatory diseases, with mitochondrial impairment ranging from impaired respiratory activity and reduced mitochondrial membrane potential to mitochondrial oxidation and fragmentation. Therefore, we developed a cell culture model that resembles an early state of inflammation-induced neuronal mitochondrial dysfunction preceding neuronal cell death, and can be used to test mito- and neuroprotective strategies. Rat primary cortical neurons were challenged with conditioned medium from mixed primary cultures of rat microglia and astrocytes that had been activated with lipopolysaccharide and ATP. When sublethal amounts of glia-conditioned medium were added to neurons for 24 h, mitochondrial membrane potential and ATP levels were decreased, whereas mitochondrial redox state remained unaffected. Effects on mitochondrial membrane potential and ATP levels were ameliorated by knock-down of the mitochondrial calcium uniporter in neurons. This study suggests that neuronal bioenergetic failure is an early event during neuroinflammation and it identifies the mitochondrial calcium uniporter as a candidate target for neuroprotection in this context.

Keywords:  Astrocytes; Energy depletion; Microglia; Mitochondria; Neuroinflammation

DOI:  https://doi.org/10.1016/j.bbrc.2022.03.120
Front Pharmacol. 2022 ;13 862085

Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases.

Juan M Suárez-Rivero, Carmen J Pastor-Maldonado, Ana Romero-González, David Gómez-Fernandez, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, José A Sánchez-Alcázar.

  Mitochondrial diseases are genetic disorders caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode mitochondrial structural or functional proteins. Although considered "rare" due to their low incidence, such diseases affect thousands of patients' lives worldwide. Despite intensive research efforts, most mitochondrial diseases are still incurable. Recent studies have proposed the modulation of cellular compensatory pathways such as mitophagy, AMP-activated protein kinase (AMPK) activation or the mitochondrial unfolded protein response (UPRmt) as novel therapeutic approaches for the treatment of these pathologies. UPRmt is an intracellular compensatory pathway that signals mitochondrial stress to the nucleus for the activation of mitochondrial proteostasis mechanisms including chaperones, proteases and antioxidants. In this work a potentially beneficial molecule, pterostilbene (a resveratrol analogue), was identified as mitochondrial booster in drug screenings. The positive effects of pterostilbene were significantly increased in combination with a mitochondrial cocktail (CoC3) consisting of: pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid and l-carnitine. CoC3 increases sirtuins' activity and UPRmt activation, thus improving pathological alterations in mutant fibroblasts and induced neurons.

Keywords:  UPRmt; mitochondrial cofactors; mitochondrial diseases; pterostilbene; sirt3

DOI:  https://doi.org/10.3389/fphar.2022.862085
Nat Rev Endocrinol. 2022 Apr 07.

Mitochondrial transfer in BAT.

Shimona Starling.

DOI: https://doi.org/10.1038/s41574-022-00674-7
Semin Cell Dev Biol. 2022 Mar 30. pii: S1084-9521(22)00095-7. [Epub ahead of print]

Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.

Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Cecilia Bucci, Christiaan Leeuwenburgh, Emanuele Marzetti.

  Mitochondrial remodeling is crucial to meet the bioenergetic demand to support muscle contractile activity during daily tasks and muscle regeneration following injury. A set of mitochondrial quality control (MQC) processes, including mitochondrial biogenesis, dynamics, and mitophagy, are in place to maintain a well-functioning mitochondrial network and support muscle regeneration. Alterations in any of these pathways compromises mitochondrial quality and may potentially lead to impaired myogenesis, defective muscle regeneration, and ultimately loss of muscle function. Among MQC processes, mitophagy has gained special attention for its implication in the clearance of dysfunctional mitochondria via crosstalk with the endo-lysosomal system, a major cell degradative route. Along this pathway, additional opportunities for mitochondrial disposal have been identified that may also signal at the systemic level. This communication occurs via inclusion of mitochondrial components within membranous shuttles named mitochondrial-derived vesicles (MDVs). Here, we discuss MDV generation and release as a mitophagy-complementing route for the maintenance of mitochondrial homeostasis in skeletal myocytes. We also illustrate the possible role of muscle-derived MDVs in immune signaling during muscle remodeling and adaptation.

Keywords:  Extracellular vesicles; Mitochondrial DNA damage; Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1016/j.semcdb.2022.03.023
Front Cell Dev Biol. 2022 ;10 837337

Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns.

Cuckoo Teresa Jetto, Akshaya Nambiar, Ravi Manjithaya.

  Macroautophagy (henceforth autophagy) an evolutionary conserved intracellular pathway, involves lysosomal degradation of damaged and superfluous cytosolic contents to maintain cellular homeostasis. While autophagy was initially perceived as a bulk degradation process, a surfeit of studies in the last 2 decades has revealed that it can also be selective in choosing intracellular constituents for degradation. In addition to the core autophagy machinery, these selective autophagy pathways comprise of distinct molecular players that are involved in the capture of specific cargoes. The diverse organelles that are degraded by selective autophagy pathways are endoplasmic reticulum (ERphagy), lysosomes (lysophagy), mitochondria (mitophagy), Golgi apparatus (Golgiphagy), peroxisomes (pexophagy) and nucleus (nucleophagy). Among these, the main focus of this review is on the selective autophagic pathway involved in mitochondrial turnover called mitophagy. The mitophagy pathway encompasses diverse mechanisms involving a complex interplay of a multitude of proteins that confers the selective recognition of damaged mitochondria and their targeting to degradation via autophagy. Mitophagy is triggered by cues that signal the mitochondrial damage such as disturbances in mitochondrial fission-fusion dynamics, mitochondrial membrane depolarisation, enhanced ROS production, mtDNA damage as well as developmental cues such as erythrocyte maturation, removal of paternal mitochondria, cardiomyocyte maturation and somatic cell reprogramming. As research on the mechanistic aspects of this complex pathway is progressing, emerging roles of new players such as the NIPSNAP proteins, Miro proteins and ER-Mitochondria contact sites (ERMES) are being explored. Although diverse aspects of this pathway are being investigated in depth, several outstanding questions such as distinct molecular players of basal mitophagy, selective dominance of a particular mitophagy adapter protein over the other in a given physiological condition, molecular mechanism of how specific disease mutations affect this pathway remain to be addressed. In this review, we aim to give an overview with special emphasis on molecular and signalling pathways of mitophagy and its dysregulation in neurodegenerative disorders.

Keywords:  mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neurodegenaration; phosphorylation; ubiquitination

DOI:  https://doi.org/10.3389/fcell.2022.837337
Front Pharmacol. 2022 ;13 854994

Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.

Shishi Liao, Jie Luo, Tulanisa Kadier, Ke Ding, Rong Chen, Qingtao Meng.

  Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.

Keywords:  damage-associated molecular patterns2; inflammation3; intestinal barrier function5; ischemia/reperfusion injury4; mitochondrial DNA1; multiple organ dysfunction syndrome7; systemic inflammatory response syndrome6

DOI:  https://doi.org/10.3389/fphar.2022.854994
Trends Pharmacol Sci. 2022 Apr 02. pii: S0165-6147(22)00057-8. [Epub ahead of print]

A novel anticancer pharmacological agent targeting mitochondrial complex I.

Gabriela Reyes-Castellanos, Alice Carrier.

  Targeting metabolic reprogramming has proven successful in oncology, but this field requires better identification of drugs that inhibit mitochondrial metabolism in cancer cells. Recent work from Dr Wolf's group reveals that the primary target of the antitumor compound SMIP004-7 is mitochondrial complex I (NDUFS2 subunit), inhibition of which promotes anticancer immune surveillance.

Keywords:  anticancer therapies; cancer metabolism; complex I; mitochondria; oxidative phosphorylation system; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tips.2022.03.007
Cell Stem Cell. 2022 Apr 07. pii: S1934-5909(22)00101-1. [Epub ahead of print]

Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.

Xinxiu Xu, Kang Jin, Abha S Bais, Wenjuan Zhu, Hisato Yagi, Timothy N Feinstein, Phong K Nguyen, Joseph D Criscione, Xiaoqin Liu, Gisela Beutner, Kalyani B Karunakaran, Krithika S Rao, Haoting He, Phillip Adams, Catherine K Kuo, Dennis Kostka, Gloria S Pryhuber, Sruti Shiva, Madhavi K Ganapathiraju, George A Porter, Jiuann-Huey Ivy Lin, Bruce Aronow, Cecilia W Lo.

  Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.

Keywords:  TUDCA; antioxidant response; congenital heart disease; endoplasmic reticulum stress; heart failure; hypoplastic left heart syndrome; i; induced pluripotent stem-cell-derived cardiomyocytes; mitochondrial permeability transition pore; oxidative stress; sildenafil

DOI:  https://doi.org/10.1016/j.stem.2022.03.003
Front Cell Dev Biol. 2022 ;10 836755

Mitochondrial Population in Mouse Eosinophils: Ultrastructural Dynamics in Cell Differentiation and Inflammatory Diseases.

Kennedy Bonjour, Cinthia Palazzi, Thiago P Silva, Kássia K Malta, Vitor H Neves, Eliane G Oliveira-Barros, Igor Neves, Victor A Kersten, Bruno T Fortuna, Amali E Samarasinghe, Peter F Weller, Christianne Bandeira-Melo, Rossana C N Melo.

  Mitochondria are multifunctional organelles of which ultrastructure is tightly linked to cell physiology. Accumulating evidence shows that mitochondrial remodeling has an impact on immune responses, but our current understanding of the mitochondrial architecture, interactions, and morphological changes in immune cells, mainly in eosinophils, is still poorly known. Here, we applied transmission electron microscopy (TEM), single-cell imaging analysis, and electron tomography, a technique that provides three-dimensional (3D) views at high resolution, to investigate mitochondrial dynamics in mouse eosinophils developing in cultures as well as in the context of inflammatory diseases characterized by recruitment and activation of these cells (mouse models of asthma, H1N1 influenza A virus (IAV) infection, and schistosomiasis mansoni). First, quantitative analyses showed that the mitochondrial area decrease 70% during eosinophil development (from undifferentiated precursor cells to mature eosinophils). Mitophagy, a consistent process revealed by TEM in immature but not in mature eosinophils, is likely operating in mitochondrial clearance during eosinophilopoiesis. Events of mitochondria interaction (inter-organelle membrane contacts) were also detected and quantitated within developing eosinophils and included mitochondria-endoplasmic reticulum, mitochondria-mitochondria, and mitochondria-secretory granules, all of them significantly higher in numbers in immature compared to mature cells. Moreover, single-mitochondrion analyses revealed that as the eosinophil matures, mitochondria cristae significantly increase in number and reshape to lamellar morphology. Eosinophils did not change (asthma) or reduced (IAV and Schistosoma infections) their mitochondrial mass in response to inflammatory diseases. However, asthma and schistosomiasis, but not IAV infection, induced amplification of both cristae numbers and volume in individual mitochondria. Mitochondrial cristae remodeling occurred in all inflammatory conditions with the proportions of mitochondria containing only lamellar or tubular, or mixed cristae (an ultrastructural aspect seen just in tissue eosinophils) depending on the tissue/disease microenvironment. The ability of mitochondria to interact with granules, mainly mobilized ones, was remarkably captured by TEM in eosinophils participating in all inflammatory diseases. Altogether, we demonstrate that the processes of eosinophilopoiesis and inflammation-induced activation interfere with the mitochondrial dynamics within mouse eosinophils leading to cristae remodeling and inter-organelle contacts. The understanding of how mitochondrial dynamics contribute to eosinophil immune functions is an open interesting field to be explored.

Keywords:  electron tomography; eosinophilopoiesis; eosinophils; mitochondria contact sites; mitochondria ultrastructure; mitochondrial architecture; mitochondrial dynamics; mouse

DOI:  https://doi.org/10.3389/fcell.2022.836755
Trends Genet. 2022 Mar 30. pii: S0168-9525(22)00039-7. [Epub ahead of print]

Genetic disorders of cellular trafficking.

Angeles García-Cazorla, Alfonso Oyarzábal, Jean-Marie Saudubray, Diego Martinelli, Carlo Dionisi-Vici.

  Cellular trafficking is essential to maintain critical biological functions. Mutations in 346 genes, most of them described in the last 5 years, are associated with disorders of cellular trafficking. Whereas initially restricted to membrane trafficking, the recent detection of many diseases has contributed to the discovery of new biological pathways. Accordingly, we propose to redesign this rapidly growing group of diseases combining biological mechanisms and clinical presentation into the following categories: (i) membrane trafficking (including organelle-related); (ii) membrane contact sites; (iii) autophagy; (iv) cytoskeleton-related. We present the most recently described pathophysiological findings, disorders and phenotypes. Although all tissues and organs are affected, the nervous system is especially vulnerable.

Keywords:  autophagy; cellular trafficking; inherited metabolic diseases; membrane contact sites; vesicular trafficking

DOI:  https://doi.org/10.1016/j.tig.2022.02.012
F S Rep. 2022 Mar;3(1): 1-2

MitoScore, MitoGrade, or MitoSure: what does embryonic mitochondrial deoxyribonucleic acid quantification actually measure and is it useful?

Richard J Paulson.

DOI: https://doi.org/10.1016/j.xfre.2022.02.001
Neurogenetics. 2022 Apr 09.

Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.

Hélio A G Teive, Carlos Henrique F Camargo, Eduardo R Pereira, Léo Coutinho, Renato P Munhoz.

  The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.

Keywords:  Genetic metabolic disorder; Hereditary spastic paraplegia; Inborn error metabolism; Spastic paraplegia; Treatable diseases

DOI:  https://doi.org/10.1007/s10048-022-00688-3
Acta Neuropathol Commun. 2022 Apr 08. 10(1): 48

Muscle histological changes in a large cohort of patients affected with Becker muscular dystrophy.

Michela Ripolone, Daniele Velardo, Stefania Mondello, Simona Zanotti, Francesca Magri, Elisa Minuti, Sara Cazzaniga, Francesco Fortunato, Patrizia Ciscato, Francesca Tiberio, Monica Sciacco, Maurizio Moggio, Paolo Bettica, Giacomo P Comi.

  Becker muscular dystrophy (BMD) is a severe X-linked muscle disease. Age of onset, clinical variability, speed of progression and affected tissues display wide variability, making a clinical trial design for drug development very complex. The histopathological changes in skeletal muscle tissue are central to the pathogenesis, but they have not been thoroughly elucidated yet. Here we analysed muscle biopsies from a large cohort of BMD patients, focusing our attention on the histopathological muscle parameters, as fibrosis, fatty replacement, fibre cross sectional area, necrosis, regenerating fibres, splitting fibres, internalized nuclei and dystrophy evaluation. We correlated histological parameters with both demographic features and clinical functional evaluations. The most interesting results of our study are the accurate quantification of fibroadipose tissue replacement and the identification of some histopathological aspects that well correlate with clinical performances. Through correlation analysis, we divided our patients into three clusters with well-defined histological and clinical features. In conclusion, this is the first study that analyses in detail the histological characteristics of muscle biopsies in a large cohort of BMD patients, correlating them to a functional impairment. The collection of these data help to better understand the histopathological progression of the disease and can be useful to validate any pharmacological trial in which the modification of muscle biopsy is utilized as outcome measure.

Keywords:  Becker muscular distrophy; Fibrosis; Histology; Muscle biopsies

DOI:  https://doi.org/10.1186/s40478-022-01354-3
Med Sci Sports Exerc. 2022 Apr 01.

Mitochondrial Mass of Naïve T Cells Is Associated with Aerobic Fitness and Energy Expenditure of Active and Inactive Adults.

Jessica R Alley, Rudy J Valentine, Marian L Kohut.

PURPOSE: Chronic exercise training is known to induce metabolic changes, but whether these adaptations extend to lymphocytes and how this may impact immune function remains largely unknown. This study was conducted to determine the extent to which mitochondrial characteristics of naïve T cells differ according to fitness status and to further examine energy production pathways of cells from aerobically trained and inactive participants.
METHODS: Blood was collected from 30 aerobically active (>six hours per week) or inactive (<90 min per week) men and women. Naïve T cell mitochondrial mass, membrane potential, and biogenesis were assessed with flow cytometry. Participants completed a treadmill maximal oxygen consumption (VO2peak) test and wore a physical activity monitor for one week. In a subset of participants, naïve CD8+ T cell activation-induced glycolytic and mitochondrial ATP production was measured.
RESULTS: Active participants exhibited 16.7% more naïve CD8+ T cell mitochondrial mass (p = 0.046), 34% greater daily energy expenditure (p < 0.001), and 39.6% higher relative VO2peak (p < 0.001), along with 33.9% lower relative body fatness (p < 0.001). Among all participants, naïve CD8+ T cell mitochondrial mass was correlated with estimated energy expenditure (r = 0.36, p = 0.048) and VO2peak (r = 0.47, p = 0.009). There were no significant differences in ATP production, mitochondrial biogenesis, or mitochondrial membrane potential between active and inactive groups.
CONCLUSIONS: This is the first study to examine the effects of aerobic exercise training status on metabolic parameters within human naïve T cells. Findings suggest that mitochondrial adaptations in certain immune cell types are positively associated with aerobic fitness and energy expenditure. This study provides a foundation for future development of prophylactic and therapeutic interventions targeting specific immune cell subsets to improve the immune response and overall health.

DOI: https://doi.org/10.1249/MSS.0000000000002914
FEBS J. 2022 Apr 03.

Dietary restriction modulates mitochondrial DNA damage and oxylipins profile in aged rats.

Artem P Gureev, Nadezda V Andrianova, Irina B Pevzner, Ljubava D Zorova, Ekaterina V Chernyshova, Irina S Sadovnikova, Dmitry V Chistyakov, Vasily A Popkov, Dmitry S Semenovich, Valentina A Babenko, Denis N Silachev, Dmitry B Zorov, Egor Y Plotnikov, Vasily N Popov.

  Age-related impairment of coordination of the processes of maintaining mitochondrial homeostasis is associated with a decrease in the functionality of cells and leads to degenerative processes. Mitochondrial DNA (mtDNA) can be a marker of oxidative stress and tissue degeneration. However, the mechanism of accumulation of age-related damage in mtDNA remains unclear. In this study, we analyzed the accumulation of mtDNA damage in several organs of rats during aging, as well as the possibility of reversing these alterations by dietary restriction (DR). We showed that mtDNA of brain compartments (with the exception of the cerebellum), along with kidney mtDNA, was the most susceptible to accumulation of age-related damage, while liver, testis, and lung were the least susceptible organs. DR prevented age-related accumulation of mtDNA damage in the cortex and led to its decrease in the lung and testis. Changes in mtDNA copy number and expression of genes involved in the regulation of mitochondrial biogenesis and mitophagy were also tissue-specific. There was a tendency for an age-related decrease in the copy number of mtDNA in the striatum and its increase in the kidney. DR promoted an increase in the amount of mtDNA in the cerebellum and hippocampus. mtDNA damage may be associated not only with the metabolic activity of organs but also with the lipid composition and activity of processes associated with the isoprostanes pathway of lipid peroxidation. The comparison of polyunsaturated fatty acids (PUFAs) and oxylipins profiles in old rats showed that DR decreased the synthesis of arachidonic acid and its metabolites synthesized by the cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), and lipoxygenase (LOX) metabolic pathways.

Keywords:  caloric restriction; mitochondria; oxidative stress; oxylipins; quality control

DOI:  https://doi.org/10.1111/febs.16451
Am J Physiol Renal Physiol. 2022 Apr 04.

Mitochondria as Mediators of Systemic Inflammation and Organ Cross-talk in Acute Kidney Injury.

Mark Hepokoski, Prabhleen Singh.

Acute kidney injury (AKI) is a systemic inflammatory disease that contributes to remote organ failures. Multiple organ failure is the leading cause of death due to AKI and lack of understanding of the mechanisms involved has precluded the development of novel therapies. Mitochondrial injury in AKI leads to mitochondrial fragmentation and release of damage associated molecular patters (DAMPs) which are known to active innate immune pathways and systemic inflammation. This review presents current evidence suggesting extracellular mitochondrial DAMPs are mediators of remote organ failures during AKI which have the potential to be modifiable.

DOI: https://doi.org/10.1152/ajprenal.00372.2021