bims-mitdyn 2020-11-01 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2020–11–01
fourteen papers selected by
Edmond Chan, Queen’s University, School of Medicine

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.
Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice.
Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy.
MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation.
Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury.
Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis.
Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cells.
The Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism.
Regulation of Ca2+ exchanges and signaling in mitochondria.
Cardiolipin deficiency in Barth syndrome is not associated with increased superoxide/H2 O2 production in heart and skeletal muscle mitochondria.
Metabolic Profiling of Single Cancer Cells Using Mitochondrial ATP Probes.
Sensitive ELISA-based detection method for the mitophagy marker p-S65-Ub in human cells, autopsy brain, and blood samples.
Association Between L-OPA1 Cleavage and Cardiac Dysfunction During Ischemia-Reperfusion Injury in Rats.
Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia.

Nat Metab. 2020 Oct 26.

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.

Yuan Zhang, Paul V Taufalele, Jesse D Cochran, Isabelle Robillard-Frayne, Jonas Maximilian Marx, Jamie Soto, Adam J Rauckhorst, Fariba Tayyari, Alvin D Pewa, Lawrence R Gray, Lynn M Teesch, Patrycja Puchalska, Trevor R Funari, Rose McGlauflin, Kathy Zimmerman, William J Kutschke, Thomas Cassier, Shannon Hitchcock, Kevin Lin, Kevin M Kato, Jennifer L Stueve, Lauren Haff, Robert M Weiss, James E Cox, Jared Rutter, Eric B Taylor, Peter A Crawford, E Douglas Lewandowski, Christine Des Rosiers, E Dale Abel.

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1-/-) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1-/- hearts. Although concurrent short-term KDs did not rescue cMPC1-/- hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.

DOI: https://doi.org/10.1038/s42255-020-00288-1
Nat Metab. 2020 Oct 26.

Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice.

Kyle S McCommis, Attila Kovacs, Carla J Weinheimer, Trevor M Shew, Timothy R Koves, Olga R Ilkayeva, Dakota R Kamm, Kelly D Pyles, M Todd King, Richard L Veech, Brian J DeBosch, Deborah M Muoio, Richard W Gross, Brian N Finck.

The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for pyruvate import into the mitochondria. Here we show that MPC1 and MPC2 expression is downregulated in failing human and mouse hearts. Mice with cardiac-specific deletion of Mpc2 (CS-MPC2-/-) exhibited normal cardiac size and function at 6 weeks old, but progressively developed cardiac dilation and contractile dysfunction, which was completely reversed by a high-fat, low-carbohydrate ketogenic diet. Diets with higher fat content, but enough carbohydrate to limit ketosis, also improved heart failure, while direct ketone body provisioning provided only minor improvements in cardiac remodelling in CS-MPC2-/- mice. An acute fast also improved cardiac remodelling. Together, our results reveal a critical role for mitochondrial pyruvate use in cardiac function, and highlight the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodelling in the setting of MPC deficiency.

DOI: https://doi.org/10.1038/s42255-020-00296-1
Nat Metab. 2020 Oct 26.

Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy.

Mariana Fernandez-Caggiano, Alisa Kamynina, Asvi A Francois, Oleksandra Prysyazhna, Thomas R Eykyn, Susanne Krasemann, Maria G Crespo-Leiro, Maria Garcia Vieites, Katiuscia Bianchi, Valle Morales, Nieves Domenech, Philip Eaton.

Cardiomyocytes rely on metabolic substrates, not only to fuel cardiac output, but also for growth and remodelling during stress. Here we show that mitochondrial pyruvate carrier (MPC) abundance mediates pathological cardiac hypertrophy. MPC abundance was reduced in failing hypertrophic human hearts, as well as in the myocardium of mice induced to fail by angiotensin II or through transverse aortic constriction. Constitutive knockout of cardiomyocyte MPC1/2 in mice resulted in cardiac hypertrophy and reduced survival, while tamoxifen-induced cardiomyocyte-specific reduction of MPC1/2 to the attenuated levels observed during pressure overload was sufficient to induce hypertrophy with impaired cardiac function. Failing hearts from cardiomyocyte-restricted knockout mice displayed increased abundance of anabolic metabolites, including amino acids and pentose phosphate pathway intermediates and reducing cofactors. These hearts showed a concomitant decrease in carbon flux into mitochondrial tricarboxylic acid cycle intermediates, as corroborated by complementary 1,2-[13C2]glucose tracer studies. In contrast, inducible cardiomyocyte overexpression of MPC1/2 resulted in increased tricarboxylic acid cycle intermediates, and sustained carrier expression during transverse aortic constriction protected against cardiac hypertrophy and failure. Collectively, our findings demonstrate that loss of the MPC1/2 causally mediates adverse cardiac remodelling.

DOI: https://doi.org/10.1038/s42255-020-00276-5
Cell Death Discov. 2020 ;6 107

MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation.

Jane E Craig, Joseph N Miller, Raju R Rayavarapu, Zhenya Hong, Gamze B Bulut, Wei Zhuang, Sadie Miki Sakurada, Jamshid Temirov, Jonathan A Low, Taosheng Chen, Shondra M Pruett-Miller, Lily Jun-Shen Huang, Malia B Potts.

  Mitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.

Keywords:  Mitophagy; Stress signalling

DOI:  https://doi.org/10.1038/s41420-020-00342-7
Cell Death Differ. 2020 Oct 27.

Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury.

Jing Huang, Ping Xie, Yuan Dong, Wei An.

Hepatic ischemic reperfusion injury (IRI) is a common complication of liver surgery. Although an imbalance between mitochondrial fission and fusion has been identified as the cause of IRI, the detailed mechanism remains unclear. Augmenter of liver regeneration (ALR) was reported to prevent mitochondrial fission by inhibiting dynamin-related protein 1 (Drp1) phosphorylation, contributing partially to its liver protection. Apart from phosphorylation, Drp1 activity is also regulated by small ubiquitin-like modification (SUMOylation), which accelerates mitochondrial fission. This study aimed to investigate whether ALR-mediated protection from hepatic IRI might be associated with an effect on Drp1 SUMOylation. Liver tissues were harvested from both humans and from heterozygous ALR knockout mice, which underwent IRI. The SUMOylation and phosphorylation of Drp1 and their modulation by ALR were investigated. Hepatic Drp1 SUMOylation was significantly increased in human transplanted livers and IRI-livers of mice. ALR-transfection significantly decreased Drp1 SUMOylation, attenuated the IRI-induced mitochondrial fission and preserved mitochondrial stability and function. This study showed that the binding of transcription factor Yin Yang-1 (YY1) to its downstream target gene UBA2, a subunit of SUMO-E1 enzyme heterodimer, was critical to control Drp1 SUMOylation. By interacting with YY1, ALR inhibits its nuclear import and dramatically decreases the transcriptional level of UBA2. Consequently, mitochondrial fission was significantly reduced, and mitochondrial function was maintained. This study showed that the regulation of Drp1 SUMOylation by ALR protects mitochondria from fission, rescuing hepatocytes from IRI-induced apoptosis. These new findings provide a potential target for clinical intervention to reduce the effects of IRI during hepatic surgery.

DOI: https://doi.org/10.1038/s41418-020-00641-7
Mol Hum Reprod. 2020 Oct 28. pii: gaaa071. [Epub ahead of print]

Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis.

Bruna M Garcia, Thiago S Machado, Karen F Carvalho, Patrícia Nolasco, Ricardo P Nociti, Maite Del Collado, Maria J D Capo Bianco, Mateus P Grejo, José Djaci Augusto Neto, Fabrícia H C Sugiyama, Katiane Tostes, Anand K Pandey, Luciana M Gonçalves, Felipe Perecin, Flávio V Meirelles, José Bento S Ferraz, Emerielle C Vanzela, Antônio C Boschero, Francisco E G Guimarães, Fernando Abdulkader, Francisco R M Laurindo, Alicia J Kowaltowski, Marcos R Chiaratti.

  Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum [ER] stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites [MERCs], changes which associate with mitofusin 2 [MFN2] repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.

Keywords:  MERC; MFN2; diabetes; endoplasmic reticulum; metabolic diseases; mitochondria; mitochondria dynamics; mtDNA; obesity; oocyte

DOI:  https://doi.org/10.1093/molehr/gaaa071
Am J Physiol Regul Integr Comp Physiol. 2020 Oct 28.

Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cells.

Sundararajan Venkatesh, Erdene Baljinnyam, Mingming Tong, Toshihide Kashihara, Lin Yan, Tong Liu, Hong Li, Lai-Hua Xie, Michinari Nakamura, Shinichi Oka, Carolyn Suzuki, Diego Fraidenraich, Junichi Sadoshima.

  Mitochondria play key roles in the differentiation and maturation of human cardiomyocytes (CMs). As human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold potential in the treatment of heart diseases, we sought to identify key mitochondrial pathways and regulators, which may provide targets for improving cardiac differentiation and maturation. Proteomic analysis was performed on enriched mitochondrial protein extracts isolated from hiPSC-CMs differentiated from dermal fibroblasts (dFCM) and cardiac fibroblasts (cFCM) at time points between 12 and 115 days of differentiation, and from adult and neonatal mouse hearts. Mitochondrial proteins with a 2-fold change at time points up to 120 days relative to 12 days were subjected to Ingenuity Pathway Analysis (IPA). The highest upregulation was in metabolic pathways for fatty acid oxidation (FAO), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) and branched chain amino acid (BCAA) degradation. The top upstream regulators predicted to be activated were peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α), the insulin receptor (IR) and the retinoblastoma protein (Rb1) transcriptional repressor. IPA and immunoblotting showed upregulation of the mitochondrial LonP1 protease - a regulator of mitochondrial proteostasis, energetics and metabolism. LonP1 knockdown increased FAO in neonatal rat ventricular cardiomyocytes (nRVMs). Our results support the notion that LonP1 upregulation negatively regulates FAO in cardiomyocytes to calibrate the flux between glucose and fatty acid oxidation. We discuss potential mechanisms by which IR, Rb1 and LonP1 regulate the metabolic shift from glycolysis to OXPHOS and FAO. These newly identified factors and pathways may help in optimizing the maturation of iPSC-CMs.

Keywords:  LonP; cardiomyocyte; mitochondria; pluripotent stem cell; proteomics

DOI:  https://doi.org/10.1152/ajpregu.00207.2020
Front Physiol. 2020 ;11 554904

The Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism.

Gaia Gherardi, Halenya Monticelli, Rosario Rizzuto, Cristina Mammucari.

  Recently, the role of mitochondrial activity in high-energy demand organs and in the orchestration of whole-body metabolism has received renewed attention. In mitochondria, pyruvate oxidation, ensured by efficient mitochondrial pyruvate entry and matrix dehydrogenases activity, generates acetyl CoA that enters the TCA cycle. TCA cycle activity, in turn, provides reducing equivalents and electrons that feed the electron transport chain eventually producing ATP. Mitochondrial Ca2+ uptake plays an essential role in the control of aerobic metabolism. Mitochondrial Ca2+ accumulation stimulates aerobic metabolism by inducing the activity of three TCA cycle dehydrogenases. In detail, matrix Ca2+ indirectly modulates pyruvate dehydrogenase via pyruvate dehydrogenase phosphatase 1, and directly activates isocitrate and α-ketoglutarate dehydrogenases. Here, we will discuss the contribution of mitochondrial Ca2+ uptake to the metabolic homeostasis of organs involved in systemic metabolism, including liver, skeletal muscle, and adipose tissue. We will also tackle the role of mitochondrial Ca2+ uptake in the heart, a high-energy consuming organ whose function strictly depends on appropriate Ca2+ signaling.

Keywords:  aerobic metabolism; mitochondria; mitochondrial calcium uniporter (MCU); mitochondrial calcium uptake; systemic metabolism

DOI:  https://doi.org/10.3389/fphys.2020.554904
Curr Opin Physiol. 2020 Oct;17 197-206

Regulation of Ca2+ exchanges and signaling in mitochondria.

Edmund J Carvalho, Peter B Stathopulos, Muniswamy Madesh.

Mitochondrial calcium (mCa2+) homeostasis also plays a key role in the buffering of cytosolic calcium (cCa2+) and calcium transported into the mitochondrial matrix regulates cellular metabolism, migration and cell fate decisions. Recent work has highlighted the importance of mCa2+ homeostasis in regulating cellular function. The discovery of the mCa2+ uptake complex has shed new light on the role of mCa2+ dynamics in cytoskeletal remodeling, mitochondrial shape and motility in cellular dynamics. Here we attempt to decipher the vast landscape of calcium regulatory effects of the mitochondria, the underlying mechanisms and the dynamics that control cellular function.

DOI: https://doi.org/10.1016/j.cophys.2020.08.010
FEBS Lett. 2020 Oct 28.

Cardiolipin deficiency in Barth syndrome is not associated with increased superoxide/H2 O2 production in heart and skeletal muscle mitochondria.

Renata L S Goncalves, Michael Schlame, Alexander Bartelt, Martin D Brand, Gökhan S Hotamışlıgil.

  Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in the gene encoding the transacylase tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial oxidants have been implicated in the cardiomyopathy in BTHS. Eleven mitochondrial sites produce superoxide/H2 O2 at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2 O2 production from each site and the ex vivo rate of superoxide/H2 O2 production in the heart and skeletal muscle mitochondria of the tafazzin knockdown mice (tazkd) from 3 to 12 months of age. Despite reduced oxidative capacity, superoxide/H2 O2 production is indistinguishable between tazkd mice and wildtype littermates. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology.

Keywords:  Barth syndrome; cardiomyopathy; mitochondria; mitochondrial reactive oxygen species (ROS); superoxide/H2O2; tafazzin; tazkd mice; “ex vivo” rate of superoxide/H2O2 production

DOI:  https://doi.org/10.1002/1873-3468.13973
STAR Protoc. 2020 Sep 18. 1(2): 100048

Metabolic Profiling of Single Cancer Cells Using Mitochondrial ATP Probes.

Thomas Rauter, Maria R Depaoli, Helmut Bischof, Wolfgang F Graier, Roland Malli.

The metabolic activity of cells is interrelated with cell signaling, functions, and fate. Uncontrolled cancer cell proliferation requires metabolic adaptations. Research focusing on understanding the characteristics of cell metabolism is crucial for the development of novel diagnostic and therapeutic strategies. Here, we describe protocols for the ATP profiling of single cancer cells by fluorescence live-cell imaging. In response to distinct metabolic inhibitions, we record individual mitochondrial ATP dynamics using established Förster resonance energy transfer-based genetically encoded fluorescent ATP probes. For complete details on the use and execution of this protocol, please refer to Depaoli et al. (2018).

DOI: https://doi.org/10.1016/j.xpro.2020.100048
Autophagy. 2020 Oct 28. 1-16

Sensitive ELISA-based detection method for the mitophagy marker p-S65-Ub in human cells, autopsy brain, and blood samples.

Jens O Watzlawik, Xu Hou, Dominika Truban, Chloe Ramnarine, Sandeep K Barodia, Tania F Gendron, Michael G Heckman, Michael DeTure, Joanna Siuda, Zbigniew K Wszolek, Clemens R Scherzer, Owen A Ross, Guojun Bu, Dennis W Dickson, Matthew S Goldberg, Fabienne C Fiesel, Wolfdieter Springer.

  Mitochondrial dysfunction is an early, imminent event in neurodegenerative disorders including Parkinson disease (PD) and Alzheimer disease (AD). The enzymatic pair PINK1 and PRKN/Parkin recognize and transiently label damaged mitochondria with ubiquitin (Ub) phosphorylated at Ser65 (p-S65-Ub) as a signal for degradation via the autophagy-lysosome system (mitophagy). Despite its discovery in cell culture several years ago, robust and quantitative detection of altered mitophagy in vivo has remained challenging. Here we developed a sandwich ELISA targeting p-S65-Ub with the goal to assess mitophagy levels in mouse brain and in human clinical and pathological samples. We characterized five total Ub and four p-S65-Ub antibodies by several techniques and found significant differences in their ability to recognize phosphorylated Ub. The most sensitive antibody pair detected recombinant p-S65-Ub chains in the femtomolar to low picomolar range depending on the poly-Ub chain linkage. Importantly, this ELISA was able to assess very low baseline mitophagy levels in unstressed human cells and in brains from wild-type and prkn knockout mice as well as elevated p-S65-Ub levels in autopsied frontal cortex from AD patients vs. control cases. Moreover, the assay allowed detection of p-S65-Ub in blood plasma and was able to discriminate between PINK1 mutation carriers and controls. In summary, we developed a robust and sensitive tool to measure mitophagy levels in cells, tissue, and body fluids. Our data strongly support the idea that the stress-activated PINK1-PRKN mitophagy pathway is constitutively active in mice and humans under unstimulated, physiological and elevated in diseased, pathological conditions. Abbreviations: Ab: antibody; AD: Alzheimer disease; AP: alkaline phosphatase; CV: coefficient of variation; ECL: electrochemiluminescence; KO: knockout; LoB: Limit of Blank; LoD: Limit of Detection; LoQ: Limit of Quantification; MSD: meso scale discovery; PD: Parkinson disease; p-S65-PRKN: phosphorylated PRKN at serine 65; p-S65-Ub: phosphorylated ubiquitin at serine 65; Std.Dev.: standard deviation; Ub: ubiquitin; WT: wild type.

Keywords:  Alzheimer disease; PINK1; PRKN; Parkin; Parkinson disease; autophagy; mitophagy; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2020.1834712
Cell Physiol Biochem. 2020 Oct 30. 54(6): 1101-1114

Association Between L-OPA1 Cleavage and Cardiac Dysfunction During Ischemia-Reperfusion Injury in Rats.

Keishla M Rodríguez-Graciani, Xavier R Chapa-Dubocq, Lee Ann MacMillan-Crow, Sabzali Javadov.

   BACKGROUND/AIMS: Structural and functional alterations in mitochondria, particularly, the inner mitochondrial membrane (IMM) plays a critical role in mitochondria-mediated cell death in response to cardiac ischemia-reperfusion (IR) injury. The integrity of IMM can be affected by two potential intra-mitochondrial factors: i) mitochondrial matrix swelling, and ii) proteolytic cleavage of the long optic atrophy type 1 (L-OPA1), an IMM-localized dynamin-like GTPase engaged in the regulation of structural organization and integrity of the mitochondrial cristae. However, the relationship between these two factors in response to oxidative stress remains unclear. Here, we elucidated the effects of cardiac IR injury on L-OPA1 cleavage and OMA1 activity.
METHODS: Langendorff-mode perfused isolated rat hearts were subjected to 25-min of global ischemia followed by 90-min reperfusion in the presence or absence of XJB-5-131 (XJB, a mitochondria-targeting ROS scavenger) and sanglifehrin A (SfA, a permeability transition pore inhibitor).
RESULTS: XJB in combination with SfA increased post-ischemic recovery of cardiac function and reduced mitochondrial ROS production at 30- and 60-min reperfusion and affected mitochondrial swelling. L-OPA1 levels were reduced in IR hearts; however, neither XJB, SfA, and their combination prevented IR-induced reduction of L-OPA1 cleavage. Likewise, IR increased the OMA1 enzymatic activity, which remained unchanged in the presence of XJB and/or SfA.
CONCLUSION: IR-induced cardiac and mitochondrial dysfunctions are associated with OMA1 activation and L-OPA1 cleavage. However, XJB, SfA, and their combination do not prevent these changes despite improved heart and mitochondria function, thus, suggesting that different mechanisms can be implicated in L-OPA1 processing in response to cardiac IR injury.

Keywords:  Cardiac ischemia-reperfusion; Mitochondria; Optic atrophy type 1 protein; Reactive oxygen species; Mitochondrial swelling; Permeability transition pores

DOI:  https://doi.org/10.33594/000000303
Mol Genet Metab. 2020 Oct 03. pii: S1096-7192(20)30197-9. [Epub ahead of print]

Biochemical phenotype and its relationship to treatment in 16 individuals with PCCB c.1606A > G (p.Asn536Asp) variant propionic acidemia.

Olivia Wenger, Miraides Brown, Brandon Smith, Devyani Chowdhury, Andrew H Crosby, Emma L Baple, Mark Yoder, William Laxen, Silvia Tortorelli, Kevin A Strauss.

  Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers. Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.

Keywords:  Biomarker; Phenotype; Propionic acidemia; Treatment

DOI:  https://doi.org/10.1016/j.ymgme.2020.09.006