title: Fus1/Tusc2 is a novel regulator of mitochondrial calcium handling, Ca2+-coupled mitochondrial processes, and Ca2+-dependent NFAT and NF-κB pathways in CD4+ T cells.
abstract: OBJECTIVE
  Fus1 has been established as mitochondrial tumor suppressor, immunomodulator, and antioxidant protein, but molecular mechanism of these activities remained to be identified. Based on putative calcium-binding and myristoyl-binding domains that we identified in Fus1, we explored our hypothesis that Fus1 regulates mitochondrial calcium handling and calcium-coupled processes.
  
  
  RESULTS
  Fus1 loss resulted in reduced rate of mitochondrial calcium uptake in calcium-loaded epithelial cells, splenocytes, and activated CD4(+) T cells. The reduced rate of mitochondrial calcium uptake in Fus1-deficient cells correlated with cytosolic calcium increase and dysregulation of calcium-coupled mitochondrial parameters, such as reactive oxygen species production, ΔμH(+), mitochondrial permeability transition pore opening, and GSH content. Inhibition of calcium efflux via mitochondria, Na(+)/Ca(2+) exchanger significantly improved the mitochondrial calcium uptake in Fus1(-/-) cells. Ex vivo analysis of activated CD4(+) T cells showed Fus1-dependent changes in calcium-regulated processes, such as surface expression of CD4 and PD1/PD-L1, proliferation, and Th polarization. Fus1(-/-) T cells showed increased basal expression of calcium-dependent NF-κB and NFAT targets but were unable to fully activate these pathways after stimulation.
  
  
  METHODS
  Our results establish Fus1 as one of the few identified regulators of mitochondrial calcium handling. Our data support the idea that alterations in mitochondrial calcium dynamics could lead to the disruption of metabolic coupling in mitochondria that, in turn, may result in multiple cellular and systemic abnormalities.
  
  
  CONCLUSIONS
  Our findings suggest that Fus1 achieves its protective role in inflammation, autoimmunity, and cancer via the regulation of mitochondrial calcium and calcium-coupled parameters.
authors: 1 Department of Biochemistry and Cancer Biology, VICC, Meharry Medical College , Nashville, Tennessee.
authors: Roman
authors: R
authors: Uzhachenko
authors: Sergey V
authors: SV
authors: Ivanov
authors: Wendell G
authors: WG
authors: Yarbrough
authors: Anil
authors: A
authors: Shanker
authors: Ruslan
authors: R
authors: Medzhitov
authors: Alla V
authors: AV
authors: Ivanova
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006706:Homeostasis; D008213:Lymphocyte Activation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011485:Protein Binding; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse; D002118:Calcium