Mitochondria dysfunction and defective protein homeostasis contribute to the onset of several neurodegenerative disorders including Friedreich's ataxia, spastic paraplegia, and Parkinson's disorder as well as normal aging. Mitochondrial protein homeostasis is maintained by localized molecular chaperones and quality control proteases. Chaperones are required for mitochondrial protein import and promote the folding of nascent or recently imported proteins while the quality control proteases degrade those proteins that fail to fold correctly. During stress, a protective mitochondrial-to-nuclear signaling pathway termed the mitochondrial unfolded protein response induces nuclear encoded mitochondrial molecular chaperone gene expression (UPRmt). ATFS-1, is unique in that it has dual compartment specific localization signals;an Nterminal mitochondrial targeting sequence and a C-terminal nuclear localization sequence. This proposal will not only show the presence of coordination of gene expression from the nuclear and mitochondrial genomes during organelle stress, but also substantiate the consequences of un-coordinated expression of the nuclear and mitochondrial genomes.

Public Health Relevance

Protein homeostasis is extremely essential and well regulated process. Impairment in this process is relevant to many diseases including cancer, neurodegenerative disorders and Aging. More specifically, decreased expression of chaperones and protein quality control has been linked to Parkinson's and spastic paraplegia (Bota and Davies 2002). During stress, one such process, an unfolded protein response, is required to upregulate the chaperones, that aid in refolding of the misfolded or unfolded proteins. If not corrected, unfolded proteins accumulate and such accumulation has been implicated in mitochondria dysfunction and aging related diseases. Due to the constant presence of ROS and accumulating mitochondrial DNA mutations, Mitochondria pose a threat from accumulating unfolded proteins. Mitochondria can combat such situations by mounting an unfolded protein response. Subsequently we also discovered cellular components required for UPRmt signaling and have shown that the pathway is essential to maintain mitochondrial function under stress conditions. In these studies, it was shown that ATFS-1, a transcription factor that drives UPRmt, can accumulate in mitochondria as well as the nucleus putting the transcription factor in correct compartments to potentially co-ordinate transcription of both the mitochondrial and nuclear genomes. A further understanding of this phenomenon will help to enhance mitochondrial function and therefore, will contribute in understanding its role in cancer and aging related disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F05-R (20))
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Reddy, Michael K
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Nargund, Amrita M; Fiorese, Christopher J; Pellegrino, Mark W et al. (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell 58:123-33