title: Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.
abstract: Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Uzhachenko
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Danyvid
authors.initials: D
authors.lastname: Olivares-Villagomez
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Goodwin
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.|Present address: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37235, USA.
authors.forename: Tanu
authors.initials: T
authors.lastname: Rana
authors.affiliation: Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA.|Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, CT 0651, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
authors.affiliation: Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, CT 0651, USA.
authors.forename: Winston J T
authors.initials: WJ
authors.lastname: Tan
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 0651, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Bondar
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 0651, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
authors.affiliation: Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, CT 0651, USA.
authors.forename: Alla V
authors.initials: AV
authors.lastname: Ivanova
mesh_terms: D050154:Adiposity / Q000235:genetics; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004734:Energy Metabolism / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D013076:Sperm Count; D013081:Sperm Motility / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C543627:Tusc2 protein, mouse; D002118:Calcium
keywords: Fus1/Tusc2; calcium response; chronic inflammation; mitochondrial Ca aging and age-related diseases 2+,; mitochondrial respiration