A mitochondrial enzyme degrades carotenoids and protects against oxidative stress.
Carotenoids are the precursors for vitamin A and are proposed to prevent oxidative damage to cells. Mammalian genomes encode a family of structurally related nonheme iron oxygenases that modify double bonds of these compounds by oxidative cleavage and cis-to-trans isomerization. The roles of the family members BCMO1 and RPE65 for vitamin A production and vision have been well established. Surprisingly, we found that the third family member, β,β-carotene-9',10'-oxygenase (BCDO2), is a mitochondrial carotenoid-oxygenase with broad substrate specificity. In BCDO2-deficient mice, carotenoid homeostasis was abrogated, and carotenoids accumulated in several tissues. In hepatic mitochondria, accumulated carotenoids induced key markers of mitochondrial dysfunction, such as manganese superoxide dismutase (9-fold), and reduced rates of ADP-dependent respiration by 30%. This impairment was associated with an 8- to 9-fold induction of phosphor-MAP kinase and phosphor-AKT, markers of cell signaling pathways related to oxidative stress and disease. Administration of carotenoids to human HepG2 cells depolarized mitochondrial membranes and resulted in the production of reactive oxygen species. Thus, our studies in BCDO2-deficient mice and human cell cultures indicate that carotenoids can impair respiration and induce oxidative stress. Mammalian cells thus express a mitochondrial carotenoid-oxygenase that degrades carotenoids to protect these vital organelles.
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44160, USA.
Jaume
J
Amengual
Glenn P
GP
Lobo
Marcin
M
Golczak
Hua Nan M
HN
Li
Tatyana
T
Klimova
Charles L
CL
Hoppel
Adrian
A
Wyss
Krzysztof
K
Palczewski
Johannes
J
von Lintig
D000818:Animals; D019556:COS Cells; D002338:Carotenoids / Q000378:metabolism*; D002522:Chlorocebus aethiops; D049308:Dioxygenases; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015723:Gene Library; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology*; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013379:Substrate Specificity
D017382:Reactive Oxygen Species; D002338:Carotenoids; D010105:Oxygenases; D049308:Dioxygenases; D044943:Fatty Acid Desaturases; C506534:BCO2 protein, human; C481678:Bco2 protein, mouse