Universität zu Köln

Supale, Sachin, Thorel, Fabrizio, Merkwirth, Carsten ORCID: 0000-0001-8895-3495, Gjinovci, Asllan, Herrera, Pedro L., Scorrano, Luca ORCID: 0000-0002-8515-8928, Meda, Paolo, Langer, Thomas ORCID: 0000-0003-1250-1462 and Maechler, Pierre ORCID: 0000-0002-2005-1433 (2013). Loss of Prohibitin Induces Mitochondrial Damages Altering beta-Cell Function and Survival and Is Responsible for Gradual Diabetes Development. Diabetes, 62 (10). S. 3488 - 3500. ALEXANDRIA: AMER DIABETES ASSOC. ISSN 1939-327X

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Abstract

Prohibitins are highly conserved proteins mainly implicated in the maintenance of mitochondrial function and architecture. Their dysfunctions are associated with aging, cancer, obesity, and inflammation. However, their possible role in pancreatic -cells remains unknown. The current study documents the expression of prohibitins in human and rodent islets and their key role for -cell function and survival. Ablation of Phb2 in mouse -cells sequentially resulted in impairment of mitochondrial function and insulin secretion, loss of -cells, progressive alteration of glucose homeostasis, and, ultimately, severe diabetes. Remarkably, these events progressed over a 3-week period of time after weaning. Defective insulin supply in -Phb2(-/-) mice was contributed by both -cell dysfunction and apoptosis, temporarily compensated by increased -cell proliferation. At the molecular level, we observed that deletion of Phb2 caused mitochondrial abnormalities, including reduction of mitochondrial DNA copy number and respiratory chain complex IV levels, altered mitochondrial activity, cleavage of L-optic atrophy 1, and mitochondrial fragmentation. Overall, our data demonstrate that Phb2 is essential for metabolic activation of mitochondria and, as a consequence, for function and survival of -cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Supale, Sachin UNSPECIFIED UNSPECIFIED UNSPECIFIED Thorel, Fabrizio UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkwirth, Carsten UNSPECIFIED orcid.org/0000-0001-8895-3495 UNSPECIFIED Gjinovci, Asllan UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrera, Pedro L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scorrano, Luca UNSPECIFIED orcid.org/0000-0002-8515-8928 UNSPECIFIED Meda, Paolo UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED orcid.org/0000-0003-1250-1462 UNSPECIFIED Maechler, Pierre UNSPECIFIED orcid.org/0000-0002-2005-1433 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-475305
DOI:	10.2337/db13-0152
Journal or Publication Title:	Diabetes
Volume:	62
Number:	10
Page Range:	S. 3488 - 3500
Date:	2013
Publisher:	AMER DIABETES ASSOC
Place of Publication:	ALEXANDRIA
ISSN:	1939-327X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INSULIN-SECRETION; PROLIFERATION; MAINTAINS; ISLETS; ROLES; DNA Multiple languages Endocrinology & Metabolism Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47530