Universität zu Köln

King, Louise E. ORCID: 0000-0003-2453-8887, Faber, Lukas ORCID: 0009-0002-5073-2923 and García‐Sáez, Ana J. ORCID: 0000-0002-3894-5945 (2026). Activator of apoptosis harakiri ( HRK ) localisation at mitochondria alters mitochondrial morphology independently of other BCL ‐2 proteins. The FEBS Journal, 293 (2). pp. 549-564. Wiley. ISSN 1742-464X

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Abstract

The activator of apoptosis harakiri (HRK) is a pro‐apoptotic BCL‐2 homology 3 (BH3)‐only protein of the apoptosis regulator Bcl‐2 (BCL‐2) family that is mainly expressed in neuronal and haematopoietic tissues. How specific HRK protein domains contribute to its pro‐apoptotic function, and what other non‐apoptotic roles HRK performs within cells, remain poorly understood. Here, we evaluated the apoptosis sensitivity, and mitochondrial shape and function of HCT116 human colorectal cells lacking all BH3‐only proteins as well as all relevant BCL‐2 proteins. By reconstituting individual BH3‐only proteins on this genetic background, we observed that HRK induces apoptosis in a manner dependent on its BH3 domain, and the presence of the apoptosis regulator BAX and BCL‐2 homologous antagonist/killer (BAK), but independent of its transmembrane domain. Intriguingly, HRK also causes mitochondrial aggregation without altering cristae structure or respiration. Although the BH3 domain is not required for mitochondrial reorganisation, we found that the transmembrane domain requires additional upstream amino acids for HRK mitochondrial localisation and reorganisation. These observations uncover a previously unknown role of HRK in modulating mitochondrial morphology that is independent of its BH3 domain and pro‐death function.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code King, Louise E. UNSPECIFIED https://orcid.org/0000-0003-2453-8887 UNSPECIFIED Faber, Lukas UNSPECIFIED https://orcid.org/0009-0002-5073-2923 UNSPECIFIED García‐Sáez, Ana J. UNSPECIFIED https://orcid.org/0000-0002-3894-5945 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-813056
Identification Number:	10.1111/febs.70255
Journal or Publication Title:	The FEBS Journal
Volume:	293
Number:	2
Page Range:	pp. 549-564
Number of Pages:	16
Date:	12 January 2026
Publisher:	Wiley
ISSN:	1742-464X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language apoptosis ; BH3 ; Harakiri ; mitochondria ; transmembrane English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81305