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Priority Research Paper|Volume 9, Issue 3|pp 627—649

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

Roman Uzhachenko1, Kelli Boyd2, Danyvid Olivares-Villagomez2, Yueming Zhu3, J. Shawn Goodwin1, Tanu Rana1,7, Anil Shanker1,5, Winston J.T. Tan5, Tanya Bondar6, Ruslan Medzhitov6, Alla V. Ivanova5
  • 1Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
  • 2Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
  • 3Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
  • 4Host-Tumor Interactions Research Program, Vanderbilt-Ingram Cancer Center, and the Center for Immunobiology, Vanderbilt University, Nashville, TN 37235, USA
  • 5Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, CT 0651, USA
  • 6Department of Immunobiology, Yale University School of Medicine, New Haven, CT 0651, USA
  • 7Present address: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37235, USA
Received: February 7, 2017Accepted: March 18, 2017Published: March 26, 2017
https://doi.org/10.18632/aging.101213

Copyright: © 2017 Uzhachenko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.