Mitochondrial Respiratory Supercomplex Association Limits Production of Reactive Oxygen Species from Complex I

Maranzana, Evelina; Barbero, Giovanna; Falasca, Anna Ida; Lenaz, Giorgio; Genova, Maria Luisa

doi:10.1089/ars.2012.4845

Cited by 362 publications

(310 citation statements)

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“…23 In particular, the supercomplex containing complexes I, III, and IV, all of which contain mtDNA-encoded subunits, along with the two electron carriers cytochrome c and ubiquinone preserves the stability of complex I, [35][36][37] and significantly curtails ROS production from this complex. 38 As predicted, tigecycline diminished the abundance of ETC supercomplexes in DLBCL cell lines, and this effect was more prominent in OxPhos-than BCR-DLBCLs (Figure 4c). …”

Section: Resultssupporting

confidence: 77%

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhosDLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. Cells adapt their metabolism to satisfy changing biosynthetic and bioenergetic needs.1,2 Investigation of metabolic reprogramming in cancer has provided insights into the metabolic control of proliferation and survival.3-5 Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. 7-12Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'. 13 Using an independent approach, the consensus cluster classification (CCC) framework compared the transcriptional profiles of DLBCL groups with each other without referencing normal B cells. 14 CCC identified tumorintrinsic distinctions in three highly reproducible clusters; the B-cell receptor/proliferation cluster (BCR-DLBCL) showing increased expression of BCR signa...

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Section: Resultssupporting

confidence: 77%

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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“…This finding is supported by in-gel enzymatic assays that demonstrate respirasome catalytic activity in a range of eukaryotes [16,24,25]. In addition, the formation of the respirasome has also been proposed to limit oxidative stress [26]. By forcing closer interactions between CI and CIII, the leakage of electrons to form superoxide is less likely.…”

Section: Oxphos Supercomplexesmentioning

confidence: 85%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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“…However, the functional and mechanistic role of supercomplexes is currently unclear and disputed (39). In future work, it will be important to determine whether the differences in respiration and ROS between neurons and astrocytes are due to the properties of the supercomplexes themselves (40), or whether the balance between the relative levels of complexes I and III is more critical. Furthermore, it will be very interesting to explore whether changes in complex I incorporation into supercomplexes and/or its balance with complex III contribute to excessive ROS associated in pathological situations, such as in the dopaminergic neuronal death in Parkinson's disease (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

López-Fabuel

Douce

Logan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

344

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Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.redox | brain | bioenergetics | lactate | glycolysis T he brain is a metabolically demanding organ (1) that requires tight cooperation between neurons and astrocytes (2). Astrocytes provide crucial metabolic and structural support (3, 4) and are key players in neurotransmission (5-7) and behavior (8). The status of many major redox couples in the brain is also regulated by astrocytes (9), through their high content of antioxidant compounds and enzymes (10) and by the constitutive stabilization of the master antioxidant transcriptional activator, nuclear factor erythroid 2-related factor 2 (Nrf2) (11). Thus, astrocytes are equipped to protect themselves when exposed to excess reactive oxygen species (ROS) (12) and reactive nitrogen species (13,14). Moreover, astrocytes also provide nearby neurons with protective antioxidant precursors through a cell-signaling mechanism involving glutamate receptor activation by neurotransmission (11,15,16). The tight coupling between astrocytes and neurons therefore helps in energy and redox metabolism during normal brain function.Intriguingly, the ATP used by neurons is supplied by oxidative phosphorylation, whereas most energy needs of astrocytes are met by glycolysis (17). In fact, the survival of neurons requires oxidative phosphorylation (18,19). The different energy metabolisms of the two cell types are closely coupled, with astrocytes releasing the glycolytic end product, lactate, which is used by neighboring neurons to drive oxidative phosphorylation (20)(21)(22). As the molecular mechanisms underlying the markedly different modes of ATP production in the two cell types are not understood, we investigated whether the organization of the mitochondrial respiratory chain in brain cells could contribute. Here, we report that the extent of supercomplex f...

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Mitochondrial Respiratory Supercomplex Association Limits Production of Reactive Oxygen Species from Complex I

Cited by 362 publications

References 78 publications

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

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