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Using mitochondrial sirtuins as drug targets: disease implications and available compounds

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Abstract

Sirtuins are an evolutionary conserved family of NAD+-dependent protein lysine deacylases. Mammals have seven Sirtuin isoforms, Sirt1–7. They contribute to regulation of metabolism, stress responses, and aging processes, and are considered therapeutic targets for metabolic and aging-related diseases. While initial studies were focused on Sirt1 and 2, recent progress on the mitochondrial Sirtuins Sirt3, 4, and 5 has stimulated research and drug development for these isoforms. Here we review the roles of Sirtuins in regulating mitochondrial functions, with a focus on the mitochondrially located isoforms, and on their contributions to disease pathologies. We further summarize the compounds available for modulating the activity of these Sirtuins, again with a focus on mitochondrial isoforms, and we describe recent results important for the further improvement of compounds. This overview illustrates the potential of mitochondrial Sirtuins as drug targets and summarizes the status, progress, and challenges in developing small molecule compounds modulating their activity.

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Abbreviations

ADH:

Aldehyde dehydrogenase

ANT:

Adenine nucleotide transporter

ECS:

Extended C-site

ELT:

Encoded library technology

ETC:

Electron transport chain

FdL:

Fluor-de-Lys

GDH:

Glutamate dehydrogenase

ICDH2:

Isocitrate dehydrogenase 2

IMS:

Intermembrane space

MCD:

Malonyl CoA decarboxylase

MDH:

Malate dehydrogenase

MLS:

Mitochondrial localization sequences

SOD:

Superoxide dismutase

Prx:

Peroxiredoxin

PTP:

Permeability transition pore

ROS:

Reactive oxygen species

TCA:

Tricarboxylic acid cycle

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Acknowledgments

We are grateful to members of the Steegborn lab and to many colleagues in the field for helpful discussions, and we apologize to those whose publications could not be covered in this review due to length limitations. Work on Sirtuins in the authors’ lab was supported by Deutsche Forschungsgemeinschaft grants STE1701/5 and STE1701/15, Alzheimer Forschung Initiative, and Oberfrankenstiftung (to CS).

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  1. Melanie Gertz

    Present address: Bayer Pharma AG, Apratherweg 18a, 42096, Wuppertal, Germany

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  1. Department of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447, Bayreuth, Germany

    Melanie Gertz & Clemens Steegborn

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Gertz, M., Steegborn, C. Using mitochondrial sirtuins as drug targets: disease implications and available compounds. Cell. Mol. Life Sci. 73, 2871–2896 (2016). https://doi.org/10.1007/s00018-016-2180-7

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