University of Pittsburgh Department of Cell Biology
  • Research

    Mitochondria are multi-functional organelles

    Mitochondria are considered to have evolved from bacteria that invaded into our ancestor cells about 300 million years ago (endosymbiotic theory). However, mitochondria have now undertaken various functions in the cells, and their existence has become indispensable for our vital activities. In addition to their well-known roles in the ATP production, mitochondria serve critical roles as an intracellular calcium ion store along with the ER, and as a place for the synthesis of intracellular small molecules such as heme, iron-sulfur cluster and steroid hormones. Mitochondria in brown adipose tissue are important for body heat production. Furthermore, for some reason, signal transduction machineries involved in the immune response against viral infection and in the execution of certain types of cell death also exist in mitochondria, and thus mitochondria function as a hub of these intracellular signal transduction pathways.

    Mitochondrial stress response

    During the process of performing such a variety of functions, mitochondria are constantly exposed to various stresses. For example, ROS, inevitable byproducts of the ATP production, damage mitochondria by oxidizing mitochondrial membrane lipids and proteins. Recent series of research have revealed that mitochondria are equipped with several strategies to cope with these stresses and maintain the quality of mitochondria. These mechanisms are called as “mitochondrial stress response” or \"mitochondrial quality control\". For example, mitophagy is a mechanism that eliminates dysfunctional mitochondria from the cells by autophagy. It has also been found that mitochondria are actively communicating with other intracellular organelles to evoke the proper stress response. For example, the accumulation of abnormal mitochondrial proteins has been shown to be signaled to the nucleus and promotes specific transcriptional program to relieve mitochondrial proteotoxic stress (mtUPR). In order to drive these mitochondrial stress responses, proteins that can monitor the abnormalities in mitochondria and transmit that information to other proteins are necessary. In our laboratory, we are interested in identifying critical molecular players in mitochondrial stress responses and elucidating their roles. Our mission is finding a clue to enhance human health through basic mitochondrial biology research.

  • Publications

    1. Sekine Y, Houston R, Eckl EM, Fessler E, Narendra DP, Jae LT, Sekine S. A mitochondrial iron-responsive pathway regulated by DELE1.. Mol Cell. 2023 Jun 15;83(12):2059-2076.e6. doi: 10.1016/j.molcel.2023.05.031. PubMed PMID: 37327776;
    2. Akabane S, Watanabe K, Kosako H, Yamashita SI, Nishino K, Kato M, Sekine S, Kanki T, Matsuda N, Endo T, Oka T. TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria.. Cell Rep. 2023 May 30;42(5):112454. doi: 10.1016/j.celrep.2023.112454. PubMed PMID: 37160114;
    3. Houston R, Sekine Y, Larsen MB, Murakami K, Mullett SJ, Wendell SG, Narendra DP, Chen BB, Sekine S. Discovery of bactericides as an acute mitochondrial membrane damage inducer.. Mol Biol Cell. 2021 Nov 1;32(21):ar32. doi: 10.1091/mbc.E21-04-0191. PubMed PMID: 34495738;
    4. Li H, Frankenfield AM, Houston R, Sekine S, Hao L. Thiol-Cleavable Biotin for Chemical and Enzymatic Biotinylation and Its Application to Mitochondrial TurboID Proteomics.. J Am Soc Mass Spectrom. 2021 Sep 1;32(9):2358-2365. doi: 10.1021/jasms.1c00079. PubMed PMID: 33909971;
    5. Liu YT, Huang X, Nguyen D, Shammas MK, Wu BP, Dombi E, Springer DA, Poulton J, Sekine S, Narendra DP. Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations.. Hum Mol Genet. 2020 Jun 3;29(9):1547-1567. doi: 10.1093/hmg/ddaa077. PubMed PMID: 32338760;
    6. Sugawara S, Kanamaru Y, Sekine S, Maekawa L, Takahashi A, Yamamoto T, Watanabe K, Fujisawa T, Hattori K, Ichijo H. The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1.. J Biol Chem. 2020 Apr 24;295(17):5588-5601. doi: 10.1074/jbc.RA119.011508. PubMed PMID: 32144202;
    7. Sekine S, Wang C, Sideris DP, Bunker E, Zhang Z, Youle RJ. Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1.. Mol Cell. 2019 Mar 7;73(5):1028-1043.e5. doi: 10.1016/j.molcel.2019.01.002. PubMed PMID: 30733118;
    8. Burman JL, Pickles S, Wang C, Sekine S, Vargas JNS, Zhang Z, Youle AM, Nezich CL, Wu X, Hammer JA, Youle RJ. Mitochondrial fission facilitates the selective mitophagy of protein aggregates.. J Cell Biol. 2017 Oct 2;216(10):3231-3247. doi: 10.1083/jcb.201612106. PubMed PMID: 28893839;
    9. Chaikuad A, Filippakopoulos P, Marcsisin SR, Picaud S, Schröder M, Sekine S, Ichijo H, Engen JR, Takeda K, Knapp S. Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly.. Structure. 2017 Jul 5;25(7):1089-1099.e3. doi: 10.1016/j.str.2017.05.020. PubMed PMID: 28648608;
    10. Sekine S, Yao A, Hattori K, Sugawara S, Naguro I, Koike M, Uchiyama Y, Takeda K, Ichijo H. The Ablation of Mitochondrial Protein Phosphatase Pgam5 Confers Resistance Against Metabolic Stress.. EBioMedicine. 2016 Mar;5():82-92. doi: 10.1016/j.ebiom.2016.01.031. PubMed PMID: 27077115;
    11. Sekine S, Kanamaru Y, Koike M, Nishihara A, Okada M, Kinoshita H, Kamiyama M, Maruyama J, Uchiyama Y, Ishihara N, Takeda K, Ichijo H. Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5.. J Biol Chem. 2012 Oct 5;287(41):34635-45. doi: 10.1074/jbc.M112.357509. PubMed PMID: 22915595;
    12. Takeda K, Komuro Y, Hayakawa T, Oguchi H, Ishida Y, Murakami S, Noguchi T, Kinoshita H, Sekine Y, Iemura S, Natsume T, Ichijo H. Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1.. Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12301-5. doi: 10.1073/pnas.0901823106. PubMed PMID: 19590015;


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