The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

Abstract

Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and remains without effective cure. Increasing evidence is supporting the mitochondrial cascade hypothesis, proposing that loss of mitochondrial fitness and subsequent ROS and ATP imbalance are important contributors to AD pathophysiology. Methods Here, we tested the effects of SUL-138, a small hibernation-derived molecule that supports mitochondrial bioenergetics via complex I/IV activation, on molecular, physiological, behavioral, and pathological outcomes in APP/PS1 and wildtype mice. Results SUL-138 treatment rescued long-term potentiation and hippocampal memory impairments and decreased beta-amyloid plaque load in APP/PS1 mice. This was paralleled by a partial rescue of dysregulated protein expression in APP/PS1 mice as assessed by mass spectrometry-based proteomics. In-depth analysis of protein expression revealed a prominent effect of SUL-138 in APP/PS1 mice on mitochondrial protein expression. SUL-138 increased the levels of proteins involved in fatty acid metabolism in both wildtype and APP/PS1 mice. Additionally, in APP/PS1 mice only, SUL-138 increased the levels of proteins involved in glycolysis and amino acid metabolism pathways, indicating that SUL-138 rescues mitochondrial impairments that are typically observed in AD. Conclusion Our study demonstrates a SUL-138-induced shift in metabolic input towards the electron transport chain in synaptic mitochondria, coinciding with increased synaptic plasticity and memory. In conclusion, targeting mitochondrial bioenergetics might provide a promising new way to treat cognitive impairments in AD and reduce disease progression.

The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function

“…Since clinical trials on modeling inflammation have been unsuccessful in sepsis, the therapeutic focus shifted toward more precise targets, such as mitochondrial-targeted therapies [ 35 , 36 ]. The novel compound SUL-138 demonstrated mitochondrial supportive effects in previous studies [ 17 , 18 , 37 ], with a specific improvement of the mitochondrial complex I and complex IV [ 17 ]. Here we show that treatment with SUL-138 supports mitochondrial function of LPS-stimulated endothelial cells and in the kidney of septic mice.…”

“…The efficacy of SUL-138 in preserving mitochondrial function, preventing endothelial cell death, and AKI in the pre-clinical models combined with the favourable safety profile from pre-clinical studies make SUL-138 a promising compound to avert organ injury in patients with sepsis [ 19 , 37 ]. However, several limitations have to be taken into account, as well as patient factors that may affect the efficacy and safety of the drug in human sepsis.…”

“…The novel compound SUL-138 was previously found to improve mitochondrial complex I and complex IV activity and limit mitochondrial oxidative stress [ 17 ] with beneficial effects in preclinical models of hypothermia/rewarming and Alzheimer’s disease [ 18 , 37 ]. Our data support these findings and add that SUL-138 supports mitochondrial function, cell survival, and organ function in both human endothelial cells and mice models of sepsis, with partially limiting inflammatory signals.…”

Mitochondrial Targeting against Alzheimer’s Disease: Lessons from Hibernation

“…The 6-chromanol derivative SUL-138 was selected as a lead compound through the screening of a small molecule library in a hypothermia-rewarming (H/R) cell model. The mode of action of SUL-138 constitutes mitochondrial complex I and IV activity preservation under pathological conditions [ 24 ], resulting in the maintenance of tissue energy levels (i.e., ATP) and a reduction in oxidative stress (i.e., ROS production and lipid peroxidation), thereby mimicking the arousal-associated mitochondrial state ( Figure 3 ). Three months of the oral administration of SUL-138 increased synaptic transmission and memory performance in both APP/PS1 and wildtype mice, similar to a single torpor/arousal cycle [ 24 ].…”

“…In addition, daily torpor in mice increases the levels of mitochondrial complex I and IV proteins, proteins involved in synaptic plasticity, long-term potentiation in the hippocampus, and restoring memory function in an AD mouse model [ 23 ]. Interestingly, mimicking arousal-induced mitochondrial changes using the 6-chromanol SUL-138, which supports complex I and IV function while suppressing ROS production, was able to mirror these effects [ 24 ]. This suggests that hibernation-associated mitochondrial regulation could be beneficial in treating AD-related synaptic and mitochondrial impairments.…”