Mitochondrial targeting strategies for the treatment of obesity and metabolic diseases

Metabolic diseases are still increasingly contributing to disabilities and early mortality in our societies.

Project information

Project duration


Project funder

Biocenter Oulu

Project coordinator

University of Oulu

Contact information

Project leader

Project description

Mitochondrial dysfunction has emerged as the major driver for the disturbed energy homeostasis and the development of metabolic complications in obesity and its related metabolic diseases. Consequently, specific mitochondrial targeting might be a novel treatment approach for these diseases. Yet, there are no specific pharmacological treatments targeting mitochondrial dysfunction. In this project, we focus on the development of known and new mitochondria activating agents for metabolic diseases. We will study the molecular mechanisms behind mitochondrial dysfunction using advanced three-dimensional (3D) peripheral tissue cell culture models and perform drug screenings in vitro. The most promising compounds will be tested in in vivo experiments. Our studies are aimed to potentially restore metabolic homeostasis in obesity and metabolic diseases.

Key publications

Lapatto H*, Kuusela M*, Heikkinen A, Muniandy M, van der Kolk BW, Gopalakrishnan S, Pöllänen N, Sandvik M, Schmidt MS, Heinonen S, Saari S, Kuula J, Hakkarainen A, Tampio J, Saarinen T, Taskinen M-R, Lundbom N, Groop P-H, Tiirola M, Katajisto P, Lehtonen M, Brenner C, Kaprio J, Pekkala S, Ollikainen M, Pietiläinen KH* and Pirinen E*. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation and gut microbiota in a twin study. *equal contribution. Sci. Adv. (2023) 9(2):eadd5163.

Vaittinen M, Ilha M, Herbers E, Wagner A, Virtanen KA, Pietiläinen KH, Pirinen E and Pihlajamäki J. Liraglutide demonstrates a therapeutic effect on mitochondrial dysfunction in human SGBS adipocytes in vitro. Diabetes Res. Clin. Pract. (2023) 199:110635.

Pirinen E#, Auranen M, Khan NA, Brilhante V, Urho N, Pessia A, Hakkarainen A, Kuula J, Heinonen U, Schmidt MS, Haimilahti K, Piirilä P, Lundbom N, Taskinen M-R, Brenner C, Velagapudi V, Pietiläinen KH and Suomalainen A#. Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy. Cell Metab. (2020) 31(6):1078-1090. #corresponding authors.

Pirinen E, Canto C, Jo YS, Morato L, Zhang H, Williams EG, Mouchiroud L, Menzies KJ, Timmers S, Imhof R, Verbeek J, Pujol A, van Loon B, Zeviani M, Schrauwen P, Sauve AA, Schoonjans K and Auwerx J. Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab. (2014) 19(6):1034-1041.

Verbeek J, Lannoo M, Pirinen E, Ryu D, Spincemaille P, van der Elst I, Windmolders P, Thevissen K, Cammue BPA, van Pelt J, Fransis S, van Eyken P, Ceuterick-De Groote C, van Veldhoven PP, Bedossa P, Nevens F, Auwerx J and Cassiman D. Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with nonalcoholic steatohepatitis. Gut (2014) 64(4):673-683.

Canto C*, Houtkooper R*, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cetour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA and Auwerx J. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. (2012) 15(6):838-847. * equal contribution

Ocobock C, Soppela P, Turunen M, Stenbäck V, Herzig KH, Rimbach R, Pontzer H. Reindeer herders from subarctic Finland exhibit high total energy expenditure and low energy intake during the autumn herd roundup. Am J Hum Biol. 2022 Apr;34(4):e23676. doi: 10.1002/ajhb.23676.

Corbin KD, Pittas AG, Desouza C, Grdinovac K, Herzig KH, Kashyap SR, Kim S, Nelson J, Rasouli N, Vickery EM, Knowler W, Pratley RE. Indices of Hepatic Steatosis and Fibrosis in Prediabetes and Association with Diabetes Development in the Vitamin D and Type 2 Diabetes Study. J Diabetes Complications. 2023 Jun;37(6):108475. doi: 10.1016/j.jdiacomp.2023.108475.

Sodum S, Mattila O, Sharma R, Remi Kamakura R, Lehto VP, Walkowiak J, Herzig KH, Ghulam Shere Raza GS. Nutrient combinations sensed by L-cell receptors potentiate GLP-1 secretion. Int. J. Mol. Sci. 2024, 25(2), 1087; doi: 10.3390/ijms25021087.

Raza GS, Kaya Y, Stenbäck V, Mutt SJ, Sharma R, Sodum N, Mattila O, Gagnon D, Järvelin MR, Tulppo M, Herzig KH, Mäkelä KA. Effect of aerobic exercise and time-restricted feeding on metabolic markers and Circadian Rhythm in Mice Fed with the High-fat Diet. Mol Nutr Food Res. 2024; in press.