Insights on targeting small molecules to the mitochondrial matrix and the preparation of MitoB and MitoP as exomarkers of mitochondrial hydrogen peroxide

Cairns, A. G., McQuaker, S. J., Murphy, M. P. and Hartley, R. C. (2021) Insights on targeting small molecules to the mitochondrial matrix and the preparation of MitoB and MitoP as exomarkers of mitochondrial hydrogen peroxide. In: Weissig, V. and Edeas, M. (eds.) Mitochondrial Medicine: Volume 1: Targeting Mitochondria. Series: Methods in molecular biology (2275). Humana: New York, NY, pp. 87-117. ISBN 9781071612613 (doi:10.1007/978-1-0716-1262-0_6)

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Abstract

Small molecules can be physicochemically targeted to the mitochondrial matrix 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 for temporal control, and can 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 signaling and implicated in the oxidative damage associated with aging and a wide range of 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 internal standards. Here we discuss the targeting of small molecules to the mitochondrial matrix using TPP, and describe the synthesis of MitoB and MitoP and the deuterated standards necessary for quantification of hydrogen peroxide in the mitochondrial matrix of whole living organisms.

Item Type:Book Sections
Status:Published
Glasgow Author(s) Enlighten ID:Cairns, Mr Andrew and Hartley, Professor Richard
Authors: Cairns, A. G., McQuaker, S. J., Murphy, M. P., and Hartley, R. C.
College/School:College of Science and Engineering > School of Chemistry
Publisher:Humana
ISBN:9781071612613
Published Online:13 June 2021

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190611METAPHEN: The Ecology of Metabolic Phenotypes: From Cells to PopulationsNeil MetcalfeEuropean Research Council (ERC)Metcalfe, Prof NeilInstitute of Biodiversity, Animal Health and Comparative Medicine