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Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.

ABSTRACT: Stable transfection manipulation with antibiotic selection and passaging induces progressive cellular senescence phenotypes. However, the underlying mechanisms remain poorly understood. This study demonstrated that stable transfection of the empty vector induced PANC-1 cells into cellular senescence. Metabolomics revealed several acylcarnitines and their upstream regulatory gene, carnitine palmitoyltransferase 1C (CPT1C) involved in fatty acid ?-oxidation in mitochondria, were strikingly decreased in senescent PANC-1 cells. Low CPT1C expression triggered mitochondrial dysfunction, inhibited telomere elongation, impaired cell survival under metabolic stress, and hindered the malignance and tumorigenesis of senescent cells. On the contrary, mitochondrial activity was restored by CPT1C gain-of-function in senescent vector PANC-1 cells. PPAR? and TP53/CDKN1A, crucial signaling components in cellular senescence, were downregulated in senescent PANC-1 cells. This study identifies CPT1C as a key regulator of stable transfection-induced progressive PANC-1 cell senescence that inhibits mitochondrial function-associated metabolic reprogramming. These findings confirm the need to identify cell culture alterations after stable transfection, particularly when cells are used for metabolomics and mitochondria-associated studies, and suggest inhibition of CPT1C could be a promising target to intervene pancreatic tumorigenesis.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7202531 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.

Wang Yongtao Y Yu Tao T Zhou Yanying Y Wang Shike S Zhou Xunian X Wang Limin L Ou Tianmiao T Chen Yixin Y Zhou Yawen Y Zhang Huizhen H Wang Ying Y Fan Xiaomei X Chen Pan P Gonzalez Frank J FJ Yu Aiming A Huang Peng P Huang Min M Bi Huichang H

Aging 20200414 8

Stable transfection manipulation with antibiotic selection and passaging induces progressive cellular senescence phenotypes. However, the underlying mechanisms remain poorly understood. This study demonstrated that stable transfection of the empty vector induced PANC-1 cells into cellular senescence. Metabolomics revealed several acylcarnitines and their upstream regulatory gene, carnitine palmitoyltransferase 1C (CPT1C) involved in fatty acid β-oxidation in mitochondria, were strikingly decreas ...[more]

PMID: 32289751

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Project description:IntroductionThe occurrence of repeated and progressive rhabdomyolysis is rare in clinical settings, particularly in adults. The pathogenesis of rhabdomyolysis is often overlooked due to its rapid recovery. Carnitine palmitoyltransferase (CPT) II deficiency could be a rare etiology of repetitive nontraumatic rhabdomyolysis, and several mutations of CPT II have been reported.Patient concernsA 41-year-old man presented with high fever, general malaise, myalgia, dyspnea, and dark-colored urine, and then progressed to anuria. In the past 15 years, he experienced dark-colored urine twice due to exercise and high fever. Physical examination revealed oliguria, suppurated tonsils, poor hemoglobin saturation, alert consciousness, normal neurological signs and reflexes, hypertension, and tachypnea. Laboratory investigations showed positive test results for inflammation, high serum myogenic enzyme levels, and evidence of acute kidney injury (AKI).DiagnosesInvestigations revealed an extremely high serum myogenic enzyme levels and impaired renal function with serum creatinine level of 510 μmol/L, consistent with the diagnosis of rhabdomyolysis, AKI stage 3, and acute respiratory distress syndrome. High levels of acylcarnitine in the serum confirmed the diagnosis of CPT II deficiency. In addition, whole exome sequencing (WES) was conducted in the patient and his mother.InterventionsIntubation, ventilator support, and hemodialysis were the major therapeutic interventions at the peak of disease progression. He was then administered valsartan tablets at a dosage of 80 mg per day and L-carnitine supplements.OutcomesWES conducted in the patient and his mother revealed 2 novel mutations of CPT II (c.482G>A and c.1493G>T) in this patient. The patient recovered from the severe AKI but the renal function remained impaired at chronic kidney disease stage 3a.ConclusionThus, gene examination can help to understand the etiology of repetitive nontraumatic rhabdomyolysis. Accurate diagnosis can be beneficial for providing an individualized treatment for patients with repeated and progressive rhabdomyolysis.

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Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.

Publications

Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence.

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