Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex

Wang, Yudong; Palmfeldt, Johan; Gregersen, Niels; Makhov, Alexander M.; Conway, James F.; Wang, Meicheng; McCalley, Stephen; Basu, Shrabani; Alharbi, Hana; Croix, Claudette St.; Calderon, Michael; Watkins, Simon C.; Vockley, Jerry

doi:10.1074/jbc.ra119.008680

Cited by 93 publications

(69 citation statements)

References 36 publications

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“…To facilitate FAO, fatty acids are transported across the mitochondrial membrane by CPT in conjunction with ACSL. This prepares the FAs to be oxidized by the mitochondria through the sequential steps in β-oxidation [23]. Therefore, the efficiency of FAO relies on the efficient transfer of electrons from β-oxidation to NADH and QH2, and ultimately to generate ATP in the ETC.…”

Section: Discussionmentioning

confidence: 99%

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

James

Varghese

Vasilyev

et al. 2020

IJMS

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The mitochondria play a vital role in controlling cell metabolism and regulating crucial cellular outcomes. We previously demonstrated that chronic inhibition of the mitochondrial complex III in rats by Antimycin A (AA) induced sustained pulmonary vasoconstriction. On the metabolic level, AA-induced mitochondrial dysfunction resulted in a glycolytic shift that was reported as the primary contributor to pulmonary hypertension pathogenesis. However, the regulatory proteins driving this metabolic shift with complex III inhibition are yet to be explored. Therefore, to delineate the mechanisms, we followed changes in the rat lung mitochondrial proteome throughout AA treatment. Rats treated with AA for up to 24 days showed a disturbed mitochondrial proteome with significant changes in 28 proteins (p < 0.05). We observed a time-dependent decrease in the expression of key proteins that regulate fatty acid oxidation, the tricarboxylic acid cycle, the electron transport chain, and amino acid metabolism, indicating a correlation with diminished mitochondrial function. We also found a significant dysregulation in proteins that controls the protein import machinery and the clearance and detoxification of oxidatively damaged peptides via proteolysis and mitophagy. This could potentially lead to the onset of mitochondrial toxicity due to misfolded protein stress. We propose that chronic inhibition of mitochondrial complex III attenuates mitochondrial function by disruption of the global mitochondrial metabolism. This potentially aggravates cellular proliferation by initiating a glycolytic switch and thereby leads to pulmonary hypertension.

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Section: Discussionmentioning

confidence: 99%

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

James

Varghese

Vasilyev

et al. 2020

IJMS

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“…While a decreased ETFDH level may be explained by reduced ETFDH expression, a more general decrease in the levels of other members of the multienergy protein complex (VLCAD and TFPα) suggests reduced stability of the complex (Wang et al, 2019). It is noteworthy that while most TFPα or TFPβ mutations affect the stability of both subunits, this patient had essentially an isolated reduction in TFPα protein.…”

Section: Discussionmentioning

confidence: 81%

“…Pathogenic variants in ETFDH result in impaired adenosine triphosphate (ATP) biosynthesis, excessive lipid accumulation in different organs and insufficient gluconeogenesis (Grünert, 2014). Recent data suggest ETFDH is part of a multiprotein energy complex, along with some of its functional partners including very long-chain acyl-CoA dehydrogenase (VLCAD) as well as the alpha and beta subunits of Trifunctional Protein (TFPα and TFPβ), where it has been shown to interact with the CoQ 10 containing core 2 subunit of Complex III of the ETC (Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial energetic impairment in a patient with late‐onset glutaric acidemia Type 2

Xiao

Astiazaran-Symonds

Basu

et al. 2020

American J of Med Genetics Pt A

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Glutaric acidemia type 2 (GA2), also called multiple acyl‐CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4–C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin‐containing dehydrogenases to Coenzyme Q10 (CoQ10) of the mitochondrial electron transport chain (ETC). We report a patient who was originally reported as the first case with primary myopathic CoQ10 deficiency when he presented at 11.5 years with exercise intolerance and myopathy that improved after treatment with ubiquinone and carnitine. At age 23, his symptoms relapsed despite increasing doses of ubiquinone and he was shown to have biallelic mutations in the ETFDH gene. Treatment with riboflavin was started and ubiquinone was changed to ubiquinol. After 4 months, the patient recovered his muscle strength with normalization of laboratory exams and exercise tolerance. Functional studies on fibroblasts revealed decreased levels of ETFDH as well as of very long‐chain acyl‐CoA dehydrogenase and trifunctional protein α. In addition, the mitochondrial mass was decreased, with increased formation of reactive oxygen species and oxygen consumption rate, but with a decreased spared respiratory capacity, and decreased adenosine triphosphate level. These findings of widespread dysfunction of fatty acid oxidation and ETC enzymes support the impairment of a larger mitochondrial ETC supercomplex in our patient.

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“…The respiratory chain is organized into interacting supercomplexes to minimize leakage of electrons and ROS formation. A recent study reports that enzymes of FAO physically interact with the NADH-binding domain of complex I of the electron transport chain (ETC), forming an integrated, multifunctional complex (44). Thus, in the absence of NADH shuttling from FAO through these supercomplexes, reverse electron transport (RET) might occur.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of Mycobacterium tuberculosis

Chandra

Zimmerman

et al. 2020

mBio

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ABSTRACT Macrophage activation involves metabolic reprogramming to support antimicrobial cellular functions. How these metabolic shifts influence the outcome of infection by intracellular pathogens remains incompletely understood. Mycobacterium tuberculosis (Mtb) modulates host metabolic pathways and utilizes host nutrients, including cholesterol and fatty acids, to survive within macrophages. We found that intracellular growth of Mtb depends on host fatty acid catabolism: when host fatty acid β-oxidation (FAO) was blocked chemically with trimetazidine, a compound in clinical use, or genetically by deletion of the mitochondrial fatty acid transporter carnitine palmitoyltransferase 2 (CPT2), Mtb failed to grow in macrophages, and its growth was attenuated in mice. Mechanistic studies support a model in which inhibition of FAO generates mitochondrial reactive oxygen species, which enhance macrophage NADPH oxidase and xenophagy activity to better control Mtb infection. Thus, FAO inhibition promotes key antimicrobial functions of macrophages and overcomes immune evasion mechanisms of Mtb. IMPORTANCE Mycobacterium tuberculosis (Mtb) is the leading infectious disease killer worldwide. We discovered that intracellular Mtb fails to grow in macrophages in which fatty acid β-oxidation (FAO) is blocked. Macrophages treated with FAO inhibitors rapidly generate a burst of mitochondria-derived reactive oxygen species, which promotes NADPH oxidase recruitment and autophagy to limit the growth of Mtb. Furthermore, we demonstrate the ability of trimetazidine to reduce pathogen burden in mice infected with Mtb. These studies will add to the knowledge of how host metabolism modulates Mtb infection outcomes.

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Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex

Cited by 93 publications

References 36 publications

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

Complex III Inhibition-Induced Pulmonary Hypertension Affects the Mitochondrial Proteomic Landscape

Mitochondrial energetic impairment in a patient with late‐onset glutaric acidemia Type 2

Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of Mycobacterium tuberculosis

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