title: Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis.
abstract: Function of the mammalian translocator protein (TSPO; previously known as the peripheral benzodiazepine receptor) remains unclear because its presumed role in steroidogenesis and mitochondrial permeability transition established using pharmacological methods has been refuted in recent genetic studies. Protoporphyrin IX (PPIX) is considered a conserved endogenous ligand for TSPO. In bacteria, TSPO was identified to regulate tetrapyrrole metabolism and chemical catalysis of PPIX in the presence of light, and in vertebrates, TSPO function has been linked to porphyrin transport and heme biosynthesis. Positive correlation between high TSPO expression in cancer cells and susceptibility to photodynamic therapy based on their increased ability to convert the precursor 5-aminolevulinic acid (ALA) to PPIX appeared to reinforce this mechanism. In this study, we used TSPO knock-out (Tspo(-/-)) mice, primary cells, and different tumor cell lines to examine the role of TSPO in erythropoiesis, heme levels, PPIX biosynthesis, phototoxic cell death, and mitochondrial bioenergetic homeostasis. In contrast to expectations, our results demonstrate that TSPO deficiency does not adversely affect erythropoiesis, heme biosynthesis, bioconversion of ALA to PPIX, and porphyrin-mediated phototoxic cell death. TSPO expression levels in cancer cells do not correlate with their ability to convert ALA to PPIX. In fibroblasts, we observed that TSPO deficiency decreased the oxygen consumption rate and mitochondrial membrane potential (ΔΨm) indicative of a cellular metabolic shift, without a negative impact on porphyrin biosynthetic capability. Based on these findings, we conclude that mammalian TSPO does not have a critical physiological function related to PPIX and heme biosynthesis.
authors.affiliation: From the Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Zhao
authors.affiliation: From the Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Lan N
authors.initials: LN
authors.lastname: Tu
authors.affiliation: the Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, and.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Mukai
authors.affiliation: the Department of Clinical Pathology, College of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Madhu P
authors.initials: MP
authors.lastname: Sirivelu
authors.affiliation: From the Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Viju V
authors.initials: VV
authors.lastname: Pillai
authors.affiliation: From the Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853.
authors.forename: Kanako
authors.initials: K
authors.lastname: Morohaku
authors.affiliation: the Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, and.
authors.forename: Roy
authors.initials: R
authors.lastname: Cohen
authors.affiliation: From the Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853,. Electronic address: vs88@cornell.edu.
authors.forename: Vimal
authors.initials: V
authors.lastname: Selvaraj
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D006418:Heme / Q000096:biosynthesis*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D011524:Protoporphyrins / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*
chemical_list: C463819:Bzrp protein, mouse; D011524:Protoporphyrins; D018079:Receptors, GABA; D006418:Heme; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX
keywords: PBR; bone marrow; cancer; mitochondria; photodynamic therapy; protoporphyrin IX