Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Henriques, Bárbara J.; Olsen, Rikke K.J.; Gomes, Cláudio M.; Bross, Peter

doi:10.1016/j.gene.2021.145407

Cited by 70 publications

(49 citation statements)

References 116 publications

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“…Multiple PPIs were also found between the subunits and assembly factors of OXPHOS complex II (CII, succinate-Q oxidoreductase complex) [24], complex III (CIII, cytochrome bc1 complex), complex IV (CIV, ubiquinol-cytochrome c oxidase complex), and complex V (CV, ATP synthase complex) [23], respectively. Other protein pairs from the same complexes identified as top hits of our in silico screen include SUCLG1-SUCLG2 and SUCLG1-SUCLA2 from the succinyl-CoA synthetase complexes [25], PDHA1-PDHB and PDHA2-PDHB from the pyruvate dehydrogenase complex [26], ETFA-ETFB from the electron transfer flavoprotein complex [27], BCKDHA-BCKDHB from the branched-chain alpha-keto acid dehydrogenase complex [28], GATB-GATC and GATC-QRSL1 from the glutaminyl-tRNA amidotransferase complex [29], and TIMM9-TIMM10 from the translocase of the inner membrane (TIM) complex [30].…”

Section: Resultsmentioning

confidence: 99%

Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling

Pei

Zhang

Cong

2021

Preprint

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Recent development of deep-learning methods has led to a breakthrough in the prediction accuracy of 3-dimensional protein structures. Extending these methods to protein pairs is expected to allow large-scale detection of protein-protein interactions and modeling protein complexes at the proteome level. We applied RoseTTAFold and AlphaFold2, two of the latest deep-learning methods for structure predictions, to analyze coevolution of human proteins residing in mitochondria, an organelle of vital importance in many cellular processes including energy production, metabolism, cell death, and antiviral response. Variations in mitochondrial proteins have been linked to a plethora of human diseases and genetic conditions. RoseTTAFold, with high computational speed, was used to predict the coevolution of about 95% of mitochondrial protein pairs. Top-ranked pairs were further subject to the modeling of the complex structures by AlphaFold2, which also produced contact probability with high precision and in many cases consistent with RoseTTAFold. Most of the top ranked pairs with high contact probability were supported by known protein-protein interactions and/or similarities to experimental structural complexes. For high-scoring pairs without experimental complex structures, our coevolution analyses and structural models shed light on the details of their interfaces, including CHCHD4-AIFM1, MTERF3-TRUB2, FMC1-ATPAF2, ECSIT-NDUFAF1 and COQ7-COQ9, among others. We also identified novel PPIs (PYURF-NDUFAF5, LYRM1-MTRF1L and COA8-COX10) for several proteins without experimentally characterized interaction partners, leading to predictions of their molecular functions and the biological processes they are involved in.

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Section: Resultsmentioning

confidence: 99%

Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling

Pei

Zhang

Cong

2021

Preprint

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“…This family includes a dozen of mitochondrial acyl-CoA dehydrogenases (ACAD), five of which are short, medium, long and very long-chain acyl-CoA dehydrogenases (SCAD, MCAD, VCAD, VLCAD1, and VLCAD2, also known as ACAD9). These are the enzymes involved in the first step of fatty acid β-oxidation [ 59 , 60 ] ( Figure 1 ). The chemical reactions performed by these ACADs lead to the production of FADH 2, the electrons of which are given to ubiquinone (Coenzyme Q 10 (CoQ 10 )) in the inner mitochondrial membrane through the electron transfer flavoprotein (ETF), thereby feeding the CoQ 10 pool of mitochondrial ETC in the same way as complex I and II [ 60 ].…”

Section: Energy Metabolism and B Vitaminsmentioning

confidence: 99%

Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Piquereau

Boitard

Ventura‐Clapier

et al. 2021

IJMS

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Heart failure (HF) is a plague of the aging population in industrialized countries that continues to cause many deaths despite intensive research into more effective treatments. Although the therapeutic arsenal to face heart failure has been expanding, the relatively short life expectancy of HF patients is pushing towards novel therapeutic strategies. Heart failure is associated with drastic metabolic disorders, including severe myocardial mitochondrial dysfunction and systemic nutrient deprivation secondary to severe cardiac dysfunction. To date, no effective therapy has been developed to restore the cardiac energy metabolism of the failing myocardium, mainly due to the metabolic complexity and intertwining of the involved processes. Recent years have witnessed a growing scientific interest in natural molecules that play a pivotal role in energy metabolism with promising therapeutic effects against heart failure. Among these molecules, B vitamins are a class of water soluble vitamins that are directly involved in energy metabolism and are of particular interest since they are intimately linked to energy metabolism and HF patients are often B vitamin deficient. This review aims at assessing the value of B vitamin supplementation in the treatment of heart failure.

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“…Unlike the oxidation of NADH which only occurs via CI, FADH 2 can be oxidized at the inner membrane mainly by CII, but also by other less abundant proteins such as the glycerol-3-phosphate dehydrogenase [14], the electron transfer flavoprotein dehydrogenases [15][16][17], the dihydroorotate dehydrogenase [18], the choline dehydrogenase [19], the sulfide CoQ reductase [20], and the proline dehydrogenase [21]. All these proteins are able to feed electrons to CoQ and in turn to CIII, which therefore can be considered the central collector delivering electrons through cytochrome c to CIV.…”

Section: Introductionmentioning

confidence: 99%

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

Rugolo

Zanna

Ghelli

2021

Life

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The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by complex V for ATP synthesis in the process of oxidative phosphorylation. Respiratory complexes are known to coexist in the membrane as single functional entities and as supramolecular aggregates or supercomplexes (SCs). Understanding the assembly features of SCs has relevant biomedical implications because defects in a single protein can derange the overall SC organization and compromise the energetic function, causing severe mitochondrial disorders. Here we describe in detail the main types of SCs, all characterized by the presence of complex III. We show that the genetic alterations that hinder the assembly of Complex III, not just the activity, cause a rearrangement of the architecture of the SC that can help to preserve a minimal energetic function. Finally, the major metabolic disturbances associated with severe SCs perturbation due to defective complex III are discussed along with interventions that may circumvent these deficiencies.

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Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease

Cited by 70 publications

References 116 publications

Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling

Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling

Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

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