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
- 1 Department of Biochemistry and Cancer Biology, School of Medicine, Meharry Medical College, Nashville, TN 37208, USA
- 2 Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- 3 Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- 4 Host-Tumor Interactions Research Program, Vanderbilt-Ingram Cancer Center, and the Center for Immunobiology, Vanderbilt University, Nashville, TN 37235, USA
- 5 Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, CT 0651, USA
- 6 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 0651, USA
- 7 Present address: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37235, USA
received: February 7, 2017 ; accepted: March 18, 2017 ; published: March 26, 2017 ;https://doi.org/10.18632/aging.101213
How to Cite
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.
ALR: ATP-linked respiration; AO: antioxidant; BR: basal respiration; Ca2+: calcium ions; [Ca2+]c: cytoplasmic Ca2+; [Ca2+]m: mitochondrial Ca2+; ETC: electron transport chain; iKEC: immortalized kidney epithelial cells; LPS: lipopolysaccharide; MDSC: myeloid-derived suppressor cells; MEF: mouse embryonic fibroblasts; mNCX: mitochondrial sodium-calcium exchanger; MCU: mitochondrial calcium uniporter; m.o.: months old; mPTP: mitochondrial permeability transition pore; mtCU: mitochondrial calcium uptake; MR: maximal respiration; MTG: MitoTracker Green; NMR: non-mitochondrial respiration; PL: proton leak; ROS: reactive oxygen species; RRC: reserve respiratory capacity; SOCE: store-operated calcium entry.