This project examines mitochondrial functioning in old age and in pathological states in which decreased energy transduction by mitochondria may compromise tissue survival. We have focused this year on mitochondrial functioning in the hearts of rats made diabetic by treatment with streptozotocin and studied in the chronic stage (6-8 weeks after treatment) of the disease. Mitochondria isolated from hearts of diabetic animals were shown to exhibit an unchanged capacity for oxidation of substrate (glutamat plus malate) and unchanged respiratory control ratios. Direct measurement of the Ca2+ gradient across the mitochondrial membrane ([Ca2+]m/[Ca2+]o) with indo-1-loaded mitochondria showed no difference between diabetic and control animals. However, studies of mitochondrial free Ca2+ concentration [Ca2+]m, in situ in single, isolated cardiac myocytes, using a fluorescence microscopy technique developed in LCS, showed that [Ca2+]m rises less in response to electrical stimulation from diabetic animals than from age- matched controls. Peak values of [Ca2+]m were 0.30 q 0.02 fM and 0.45 q 0.02 fM for diabetic and control animals respectively: the difference is significant (p<0.05). However, values of resting, non-stimulated [Ca2+]m were higher in cells from the diabetic animals (0.13 q 0.01 fM vs 0.07 q 0.01 fM for diabetic and control, respectively). Together, these results suggest a lesion in excitation-contraction coupling mechanisms in this mode of diabetic cardiomyopathy - a proposal that could be tested directly by measurements of cytosol free Ca2+. The failure of [Ca2+]m to rise to as great an extent on stimulation of the myocytes from the diabetic animal could underlie the failure to activate pyruvate oxidation, as described elsewhere.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000231-10
Application #
3745456
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code