title: Targeting mitochondria with small molecules: the preparation of MitoB and MitoP as exomarkers of mitochondrial hydrogen peroxide.
abstract: Small molecules can be physicochemically targeted to mitochondria using the lipophilic alkyltriphenylphosphonium (TPP) group. Once in the mitochondria the TPP-conjugate can detect or influence processes within the mitochondrial matrix directly. Alternatively, the conjugate can behave as a prodrug, which is activated by release from the TPP group either using an internal or external instruction. Small molecules can be designed that can be used in any cell line, tissue or whole organism, allow temporal control, and be applied in a reversible dose-dependent fashion. An example is the detection and quantification of hydrogen peroxide in mitochondria of whole living organisms by MitoB. Hydrogen peroxide produced within the mitochondrial matrix is involved in signalling and implicated in the oxidative damage associated with aging and a wide range of age-associated conditions including cardiovascular disease, neurodegeneration, and cancer. MitoB accumulates in mitochondria and is converted into the exomarker, MitoP, by hydrogen peroxide in the mitochondrial matrix. The hydrogen peroxide concentration is determined from the ratio of MitoP to MitoB after a period of incubation, and this ratio is determined by mass spectrometry using d15-MitoP and d15-MitoB as standard. Here we describe the synthesis of MitoB and MitoP and the deuterated standards necessary for this method of quantification.
authors: WestCHEM School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK.
authors: Andrew G
authors: AG
authors: Cairns
authors: Stephen J
authors: SJ
authors: McQuaker
authors: Michael P
authors: MP
authors: Murphy
authors: Richard C
authors: RC
authors: Hartley
mesh_terms: D055808:Drug Discovery / Q000379:methods; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010636:Phenols / Q000138:chemical synthesis / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C558697:MItoB compound; C558698:MItoP compound; D009943:Organophosphorus Compounds; D010636:Phenols; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide