Abstract Body: Background: The brain and its neuronal homeostasis relies on mitochondrial health. Mitochondrial dysfunctions, oxidative stress contribute to neurodegenerative disorders. However, the link between cardiac mitochondrial dysfunction and brain impairments remains unclear. Hypothesis: We hypothesize that cardiac mitochondrial dysfunction cross-talks to the brain in a region-specific manner and leads to neuronal adaptive changes by triggering oxidative stress and mitochondrial function impairment. Methods: We induced heart failure in mice within 21 days by deleting Lonp1 in the cardiomyocytes (Lonp1cKO) compared alongside with cre-control and partial (50%) deletion of Lonp1 (Lonp1HetcKO) mice. We measured cerebral blood flow (CBF) using Laser speckle contrast imaging, locomotor activity through CLAMS, region-specific mitochondrial function analysis, oxidative stress by electron paramagnetic resonance (EPR), protein expression by Western blot, and neuronal morphology by histology. Statistical analysis was performed using One-way ANOVA followed by Tukey’s post hoc test with significance set at a p-value< 0.05. Results: The cerebral blood flow in Lonp1cKO mice showed a significant (p<0.0001) reduction (587.1±33.68, n=7) when compared to cre-control (1034±31.26, n=5); in contrast, a significant increase blood flow was observed in Lonp1HetcKO (1233±46.90, n=7) at 21 days. Additionally, both hippocampus of Lonp1HetcKO (n=6) and Lonp1cKO (n=6), when compared to control show a significant reduction in mitochondrial complex I (127±8.9) vs (82.6±20.1) vs (147.2±13.3), complex II (204.2±6.7) vs (152.7±7.7) vs (189.8±5.2), complex III (597.3±47) vs (484.7±24.8) vs (776.6±47.1), complex IV (168.6±18.2) vs (69.1±16.2) vs (177.3±9.4) and complex V (411.3±42.4) vs (508.1±48.1) vs (669.4±27.5), and similar trend observed in the cortex. Immunoblot analysis revealed significant upregulation of ATF4, ATF5, and downregulation of OPA1 proteins in LonpP1cKO compared to cre-control and EPR spectrum analysis showed a significantly (38.06±1.8) vs (30.09±0.8) increased oxidative stress in in the cortex of Lonp1cKO mice compared to cre-control. Conclusion: In conclusion, mitochondrial dysfunction led to a manifestation of neuropathological events in LonP1cKO mice that led to mitochondrial metabolic remodelling and cellular stress response in the post-mitotic neuronal brain cells, suggesting an intertwined network between the heart and the brain via mitochondrial stress response pathway.