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Biochim Biophys Acta Mol Basis Dis. 2019 Apr 1;1865(4):854-866. doi: 10.1016/j.bbadis.2018.10.012. Epub 2018 Oct 17.

Alternative respiratory chain enzymes: Therapeutic potential and possible pitfalls.

Author information

1
Faculty of Medicine and Life Sciences, BioMediTech Institute and Tampere University Hospital, FI-33014, University of Tampere, Finland. Electronic address: sina.saari@uta.fi.
2
Departamento de Tecnologia, Faculdade de Ciências Agrárias e Veterinárias, Universidade Estadual Paulista "Júlio de Mesquita Filho", 14884-900 Jaboticabal, SP, Brazil. Electronic address: geovanagarcia@grad.fcav.unesp.br.
3
Faculty of Medicine and Life Sciences, BioMediTech Institute and Tampere University Hospital, FI-33014, University of Tampere, Finland. Electronic address: katharina.bremer@queensu.ca.
4
Departamento de Tecnologia, Faculdade de Ciências Agrárias e Veterinárias, Universidade Estadual Paulista "Júlio de Mesquita Filho", 14884-900 Jaboticabal, SP, Brazil. Electronic address: marina.chioda@posgrad.fcav.unesp.br.
5
Faculty of Medicine and Life Sciences, BioMediTech Institute and Tampere University Hospital, FI-33014, University of Tampere, Finland. Electronic address: ana.andjelkovic@uta.fi.
6
Department of Biology, FI-20014, University of Turku, Finland; Faculty of Biological and Environmental Sciences, FI-00014, University of Helsinki, Finland. Electronic address: paul.debes@dal.ca.
7
Department of Biology, FI-20014, University of Turku, Finland. Electronic address: miknik@utu.fi.
8
Faculty of Medicine and Life Sciences, BioMediTech Institute and Tampere University Hospital, FI-33014, University of Tampere, Finland. Electronic address: marten.szibor@uta.fi.
9
Faculty of Medicine and Life Sciences, BioMediTech Institute and Tampere University Hospital, FI-33014, University of Tampere, Finland. Electronic address: eric.dufour@uta.fi.
10
INSERM UMR1141, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France. Electronic address: pierre.rustin@inserm.fr.
11
Departamento de Tecnologia, Faculdade de Ciências Agrárias e Veterinárias, Universidade Estadual Paulista "Júlio de Mesquita Filho", 14884-900 Jaboticabal, SP, Brazil. Electronic address: marcos.t.oliveira@unesp.br.
12
Faculty of Medicine and Life Sciences, BioMediTech Institute and Tampere University Hospital, FI-33014, University of Tampere, Finland; Institute of Biotechnology, FI-00014, University of Helsinki, Finland. Electronic address: howard.t.jacobs@uta.fi.

Abstract

The alternative respiratory chain (aRC), comprising the alternative NADH dehydrogenases (NDX) and quinone oxidases (AOX), is found in microbes, fungi and plants, where it buffers stresses arising from restrictions on electron flow in the oxidative phosphorylation system. The aRC enzymes are also found in species belonging to most metazoan phyla, including some chordates and arthropods species, although not in vertebrates or in Drosophila. We postulated that the aRC enzymes might be deployed to alleviate pathological stresses arising from mitochondrial dysfunction in a wide variety of disease states. However, before such therapies can be contemplated, it is essential to understand the effects of aRC enzymes on cell metabolism and organismal physiology. Here we report and discuss new findings that shed light on the functions of the aRC enzymes in animals, and the unexpected benefits and detriments that they confer on model organisms. In Ciona intestinalis, the aRC is induced by hypoxia and by sulfide, but is unresponsive to other environmental stressors. When expressed in Drosophila, AOX results in impaired survival under restricted nutrition, in addition to the previously reported male reproductive anomalies. In contrast, it confers cold resistance to developing and adult flies, and counteracts cell signaling defects that underlie developmental dysmorphologies. The aRC enzymes may also influence lifespan and stress resistance more generally, by eliciting or interfering with hormetic mechanisms. In sum, their judicious use may lead to major benefits in medicine, but this will require a thorough characterization of their properties and physiological effects.

KEYWORDS:

AOX; Mitochondria; Mitochondrial disease; Reactive oxygen species; Thermogenesis

PMID:
30342157
DOI:
10.1016/j.bbadis.2018.10.012
[Indexed for MEDLINE]
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