Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations

Leoni, Valerio; Strittmatter, Laura; Zorzi, Giovanna; Zibordi, Federica; Dusi, Sabrina; Garavaglia, Barbara; Venco, Paola; Caccia, Claudio; Souza, Amanda; Deik, Amy; Clish, Clary B.; Rimoldi, M.; Ciusani, Emilio; Bertini, Enrico; Nardocci, Nardo; Mootha, Vamsi K.; Tiranti, Valeria

doi:10.1016/j.ymgme.2011.12.005

Cited by 110 publications

(80 citation statements)

References 44 publications

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“…We use a previously described metabolic profiling platform (13)(14)(15)(16)(17) that interrogates 242 metabolites, including 132 polar and 110 lipids (Table S2). We began by identifying metabolites whose levels at rest differed between patient and control groups.…”

Section: Resultsmentioning

confidence: 99%

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Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy

Delaney

Sharma

Tadvalkar

et al. 2017

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

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McArdle disease and mitochondrial myopathy impair muscle oxidative phosphorylation (OXPHOS) by distinct mechanisms: the former by restricting oxidative substrate availability caused by blocked glycogen breakdown, the latter because of intrinsic respiratory chain defects. We applied metabolic profiling to systematically interrogate these disorders at rest, when muscle symptoms are typically minimal, and with exercise, when symptoms of premature fatigue and potential muscle injury are unmasked. At rest, patients with mitochondrial disease exhibit elevated lactate and reduced uridine; in McArdle disease purine nucleotide metabolites, including xanthine, hypoxanthine, and inosine are elevated. During exercise, glycolytic intermediates, TCA cycle intermediates, and pantothenate expand dramatically in both mitochondrial disease and control subjects. In contrast, in McArdle disease, these metabolites remain unchanged from rest; but urea cycle intermediates are increased, likely attributable to increased ammonia production as a result of exaggerated purine degradation. Our results establish skeletal muscle glycogen as the source of TCA cycle expansion that normally accompanies exercise and imply that impaired TCA cycle flux is a central mechanism of restricted oxidative capacity in this disorder. Finally, we report that resting levels of long-chain triacylglycerols in mitochondrial myopathy correlate with the severity of OXPHOS dysfunction, as indicated by the level of impaired O 2 extraction from arterial blood during peak exercise. Our integrated analysis of exercise and metabolism provides unique insights into the biochemical basis of these muscle oxidative defects, with potential implications for their clinical management. mitochondria | McArdle disease | exercise physiology | metabolic profiling | TCA expansion

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Section: Resultsmentioning

confidence: 99%

“…Samples were coded and de-identified before further analysis. Samples were analyzed at the Broad Institute using methods that have been previously described (13)(14)(15)(16)(17). In total, 173 plasma samples were analyzed and 252 metabolites were detected ( Table S2).…”

Section: Methodsmentioning

confidence: 99%

Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy

Delaney

Sharma

Tadvalkar

et al. 2017

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

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“…After 24 h, proteins secreted in the medium (secretome) by TPC-1 cells were collected and identified, as previously described (Caccia et al 2011). Also, after 24 h, TPC-1 cells treated with 100 mM 4-IPP were lysed; the lysate was analyzed by isotope dilution mass spectrometry, as previously described (Leoni et al 2012).…”

Section: Nlc-ms/ms Analysis and Isotope Dilution Mass Spectrometry Anmentioning

confidence: 99%

“…7A). We also performed isotope-dilution gas chromatography mass spectrometry (GC-MS) analysis (Leoni et al 2012) of cellular lysates after 24 h 4-IPP treatment. We found that lactate, pyruvate, and malate were elevated and citrate and fumarate were reduced (Fig.…”

Section: Mif Inhibition Produces Proteomic and Metabolic Changesmentioning

confidence: 99%

4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

Varinelli¹,

Caccia²,

Volpi³

et al. 2015

Endocrine-Related Cancer

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Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is over-expressed in several human neoplastic cells. When MIF binds its receptor (CD74) and co-receptor (CD44), it initiates signaling cascades that orchestrate cell proliferation and survival, and it can directly modulate the activity of AMPK. These activities indicate that MIF potentially regulates cell survival and metabolism. We found that MIF was primarily co-expressed with CD74 in 16 out of 23 papillary thyroid carcinoma (PTC) and in all the 27 available anaplastic thyroid carcinoma (ATC) biopsy samples. MIF and CD74 were co-expressed in TPC-1 and HTC-C3 cell lines. The selective MIF inhibitor, 4-iodo-6-phenylpyrimidine (4-IPP), blocked MIF/CD74 internalization, activated JNK, and dosedependently inhibited proliferation inducing apoptosis and mitotic cell death. In two CD74-negative cell lines, NIM-1 and K1, 4-IPP treatment partially reduced proliferation. Coordinated MIF and CD74 expression appeared to confer in tumor cells the plasticity necessary to escape cell cycle regulation, metabolic changes, and stress conditions. MIF/CD74 signaling removal made cells susceptible to apoptosis and mitotic cell death. This finding suggests a possible avenue for targeting DNA endoreduplication, thus preventing the proliferation of therapy-resistant cell subpopulations. This study highlights MIF/CD74 axis as an important player in the biology of aggressive thyroid neoplasms.

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“…PANK2 is mainly targeted to mitochondria, its mutation may therefore also cause dysfunction of cellular energy metabolism [73]. Indeed, a recent study examining blood metabolic profiles in PKAN documented elevated levels of lactate suggesting mitochondrial dysfunction and reduced levels of triglycerides, cholesterol metabolites and sphingomyelins confirming the role of PANK2 in the lipid metabolism [74]. It has been hypothesized that the alteration of ferroportin (FPN1) expression mediated by PANK2 might be the link to accumulation of iron in the brain [75].…”

Section: Genetic Testing and Molecular Findings In Pkanmentioning

confidence: 99%

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Schneider

Dušek²,

Hardy³

et al. 2013

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Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic.Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

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Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations

Cited by 110 publications

References 44 publications

Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy

Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy

4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

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