CORE D: MITOCHONDRIAL STRUCTURE AND FUNCTION ? SUMMARY/ABSTRACT Recent findings of this PO1 revealed that treatment of aged mice with the mitochondria-targeted peptide (SS- 31) conferred rapid rejuvenation of mitochondrial bioenergetics, suggesting that SS-31 increases intrinsic mitochondrial plasticity by increasing the capacity of the mitochondrial ETC to produce more ATP at times of increased metabolic demands or decreased fuel supply. The mechanism by which SS-31 increases mitochondrial plasticity is not completely understood, although recent work the Program Project and this Core has now shown that these peptides target the inner mitochondrial membrane (IMM) because of their high affinity for cardiolipin (CL). By modifying the interaction of CL and cytochrome c (cyt c), SS peptides protect the hexacoordination of the heme Fe to optimize electron transport (ET) and minimize reactive oxygen species (ROS) production. As a result, the SS peptides prevent oxidative stress in the mitochondrial inter membrane space (IMS). The goal of this Mitochondrial Structure and Function Core is to assist all Projects in the PO1 to demonstrate that protection of mitochondrial structure by the SS peptides at the level of cristae architecture and cytochrome c (cyt c) heme ligation can reduce mitochondrial aging in the heart, skeletal muscle and retina. The major services provided by this Core include:
Aim 1 is to provide ultrastructural and protein characterization of age and high fat diet-mediated changes in cristae architecture and composition, and protection by SS peptides.
Aim 2 is to provide characterization of age- and high fat diet-mediated changes in cyt c heme structure, and protection by SS peptides. This will include providing the resources to assist all Projects in determining the extent of oxidative stress in the mitochondrial IMS and working with Core B to obtain mass-spectrometry confirmation of these oxidized proteins.
Aim 3 is to provide methods for studying mitochondrial electron transport chain structures. This will include methods for identifying supercomplexes in mitochondria from retina, heart and skeletal muscles using 2-D native blue gels/SDS gel electrophoresis and specific antibodies for the individual respiratory complex proteins. In summary, this Core will determine if structural changes in mitochondrial cristae and cyt c heme ligation play a role in the inhibition of ET and increase in ROS emission associated with aging. The SS peptides will provide evidence to support the importance of repairing mitochondrial structure in order to restore cellular bioenergetics and allow for repair of cellular structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG001751-33A1
Application #
9209220
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O2))
Project Start
1997-08-15
Project End
2022-03-31
Budget Start
2017-01-15
Budget End
2017-08-31
Support Year
33
Fiscal Year
2017
Total Cost
$257,373
Indirect Cost
$14,591
Name
University of Washington
Department
Type
Domestic Higher Education
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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