Propagation of age-dependent mitochondrial damage in the rat heart

Objectives Aging is leading independent risk factor of many major diseases, yet knowledge of the underlying molecular mechanisms and kinetics at the intact animal levels is scarce. Mitochondrial dysfunction, expressed by decline of organelle’s membrane potential (ΔΨm), is a key mechanism of cellular senescence. Previous cardiac PET studies of the ΔΨm probe F-18-fluorobenzyl triphenyl phosphonium (FBnTP) in 24-mo-old rats suggested that mitochondrial damage is most pronounced in the lateral wall. Here, we expand this study to document evolution kinetics of mitochondrial dysfunction over age, as correlated with oxidative stress (OS).

Methods FBnTP PET was carried out in 26 rats (Fisher and Brown Norway, BN) at age 6 to 24 months (1 mCi IV, 30-min static scan acquired after 20-min uptake time). Myocardial blood flow was assessed by N-13-ammonia PET (1 mCi IV, 20-min static scan, 5 min uptake time). CT scan was acquired for image co-registration. Tissue samples were collected for gamma well counting of FBnTP. OS was assessed by aconitase assay.

Results FBnTP distribution in the LV wall of 6-mo-old rats was highly uniform, whereas in 12-mo-old a limited focal decrease of uptake was measured in the lateral wall. Extent of decrease of FBnTP myocardial uptake propagated with age to encompass a significant portion of the free wall in 24-mo-old rats. Severity of mitochondrial damage detected by FBnTP PET was more pronounced in Fisher than BN rats. Global FBnTP uptake and aconitase activity in the LV wall decreased with age. Spatial correlation was found between LV segments of decreased FBnTP uptake and decline of aconitase activity.

Conclusions This finding demonstrates for the first time that mitochondria-mediated myocardial aging in rats may begin as a focal process propagating with age to adjacent regions of LV wall. Implementation of FBnTP PET technology to human studies may allow dramatic advance in the development of therapeutic and preventive strategies in aging of the heart and other organs.

Research Support NIH/NI