Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts.
Four of the 5 biotin-dependent carboxylases (BDC) are in the mitochondria. BDC replace intermediates in the Krebs [tricarboxylic acid (TCA)] cycle that are regularly removed for the synthesis of key metabolites such as heme or amino acids. Heme, unlike amino acids, is not recycled to regenerate these intermediates, is not utilized from the diet, and must be synthesized in situ. We studied whether biotin deficiency (BD) lowers heme synthesis and whether mitochondria would be disrupted. Biotin-deficient medium was prepared by using bovine serum stripped of biotin with charcoal/dextran or avidin. Biotin-deficient primary human lung fibroblasts (IMR90) lost their BDC and senesced before biotin-sufficient cells. BD caused heme deficiency; there was a decrease in heme content and heme synthesis, and biotin-deficient cells selectively lost mitochondrial complex IV, which contains heme-a. Loss of complex IV, which is part of the electron transport chain, triggered oxidant release and oxidative damage, hallmarks of heme deficiency. Restoring biotin to the biotin-deficient medium prevented the above changes. Old cells were more susceptible to biotin shortage than young cells. These findings highlight the biochemical connection among biotin, heme, and iron metabolism, and the mitochondria, due to the role of biotin in maintaining the biochemical integrity of the TCA cycle. The findings are discussed in relation to aging and birth defects in humans.
Atamna
Hani
H
Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
Newberry
Justin
J
Erlitzki
Ronit
R
Schultz
Carla S
CS
Ames
Bruce N
BN
D001710:Biotin / Q000172:deficiency*; D002851:Chromatography, High Pressure Liquid; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006418:Heme / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D016877:Oxidants / Q000378:metabolism
D016877:Oxidants; D006418:Heme; D001710:Biotin