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SIRT5 regulation of ammonia-induced autophagy and mitophagy.

Title data

Polletta, Lucia ; Vernucci, Enza ; Carnevale, Ilaria ; Arcangeli, Tania ; Rotili, Dante ; Palmerio, Silvia ; Steegborn, Clemens ; Nowak, Theresa ; Schutkowski, Mike ; Pellegrini, Laura ; Sansone, Luigi ; Villanova, Lidia ; Runci, Alessandra ; Pucci, Bruna ; Morgante, Emanuela ; Fini, Massimo ; Mai, Antonello ; Russo, Matteo A. ; Tafani, Marco:
SIRT5 regulation of ammonia-induced autophagy and mitophagy.
In: Autophagy. Vol. 11 (February 2015) Issue 2 . - pp. 253-270.
ISSN 1554-8635
DOI: https://doi.org/10.1080/15548627.2015.1009778

Abstract in another language

In liver the mitochondrial sirtuin, SIRT5, controls ammonia detoxification by regulating CPS1, the first enzyme of the urea cycle. However, while SIRT5 is ubiquitously expressed, urea cycle and CPS1 are only present in the liver and, to a minor extent, in the kidney. To address the possibility that SIRT5 is involved in ammonia production also in nonliver cells, clones of human breast cancer cell lines MDA-MB-231 and mouse myoblast C2C12, overexpressing or silenced for SIRT5 were produced. Our results show that ammonia production increased in SIRT5-silenced and decreased in SIRT5-overexpressing cells. We also obtained the same ammonia increase when using a new specific inhibitor of SIRT5 called MC3482. SIRT5 regulates ammonia production by controlling glutamine metabolism. In fact, in the mitochondria, glutamine is transformed in glutamate by the enzyme glutaminase, a reaction producing ammonia. We found that SIRT5 and glutaminase coimmunoprecipitated and that SIRT5 inhibition resulted in an increased succinylation of glutaminase. We next determined that autophagy and mitophagy were increased by ammonia by measuring autophagic proteolysis of long-lived proteins, increase of autophagy markers MAP1LC3B, GABARAP, and GABARAPL2, mitophagy markers BNIP3 and the PINK1-PARK2 system as well as mitochondrial morphology and dynamics. We observed that autophagy and mitophagy increased in SIRT5-silenced cells and in WT cells treated with MC3482 and decreased in SIRT5-overexpressing cells. Moreover, glutaminase inhibition or glutamine withdrawal completely prevented autophagy. In conclusion we propose that the role of SIRT5 in nonliver cells is to regulate ammonia production and ammonia-induced autophagy by regulating glutamine metabolism.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 25700560
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: Yes
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 20 Apr 2015 15:11
Last Modified: 20 Apr 2015 15:11
URI: https://eref.uni-bayreuth.de/id/eprint/10437