Mitochondrial Targeting against Alzheimer's Disease: Lessons from Hibernation

Abstract

Alzheimer's disease (AD) is the most common cause of dementia worldwide and yet remains without effective therapy. Amongst the many proposed causes of AD, the mitochondrial cascade hypothesis is gaining attention. Accumulating evidence shows that mitochondrial dysfunction is a driving force behind synaptic dysfunction and cognitive decline in AD patients. However, therapies targeting the mitochondria in AD have proven unsuccessful so far, and out-of-the-box options, such as hibernation-derived mitochondrial mechanisms, may provide valuable new insights. Hibernators uniquely and rapidly alternate between suppression and re-activation of the mitochondria while maintaining a sufficient energy supply and without acquiring ROS damage. Here, we briefly give an overview of mitochondrial dysfunction in AD, how it affects synaptic function, and why mitochondrial targeting in AD has remained unsuccessful so far. We then discuss mitochondria in hibernation and daily torpor in mice, covering current advancements in hibernation-derived mitochondrial targeting strategies. We conclude with new ideas on how hibernation-derived dual mitochondrial targeting of both the ATP and ROS pathways may boost mitochondrial health and induce local synaptic protein translation to increase synaptic function and plasticity. Further exploration of these mechanisms may provide more effective treatment options for AD in the future.

Keywords: Alzheimer’s disease; SUL-138; daily torpor; hibernation-derived compound; mitochondrial dysfunction.

Figure 1

Mitochondrial impairments in AD. The major energy source for the brain is glucose, which is metabolized to ATP via glycolysis, pyruvate metabolism, the tricarboxylic acid (TCA) cycle, and the oxidative phosphorylation system (OXPHOS) via complexes I–V in the electron transport chain. Mitochondria also produce ROS as by-products of activity in the OXPHOS system. Other, less prominent inputs into the OXPHOS system are via fatty acid degradation and oxidation (FAD and FAO) and amino acid metabolism. In AD, excess levels of ROS, probably due to aging-related generation from complexes I and III, leads to oxidative damage to enzymes involved in glycolysis/pyruvate metabolism, the TCA cycle, and the OXPHOS system, thus augmenting ATP deficits, and ultimately leading to high ROS and low ATP levels found in AD (red arrows).

Figure 2

Mitochondrial regulation during hibernation. During the torpor phase of hibernation, glycolysis is halted and remaining energy metabolism shifts to fatty acid metabolism (FAD and FAO) (purple arrows). Enzymes involved in glycolysis, pyruvate metabolism, and the TCA cycle are reduced and/or less efficient. Efficiencies of complexes I and II of the OXPHOS system are drastically reduced through reduced input from the TCA cycle, and posttranslational modifications and allosteric hindrance by oxaloacetate (OAA), an accumulated TCA cycle intermediate. Increased levels of H₂S due to decreased H₂S oxidation efficiency of SQR and increased production of H₂S by CBS, in turn inhibit complex IV function. ROS damage is prevented due to the downregulation of complex I, which normally produces a large fraction of ROS in the OXPHOS system. In addition, UCP1 upregulation leads to uncoupling of the OXPHOS system, thereby altering its redox state and inhibiting ROS production. Finally, antioxidant levels, e.g., ascorbate, are higher during hibernation, directly neutralizing ROS.

Figure 3

Targeting ATP/ROS balance via mitochondrial stimulation with SUL-138. During arousal from torpor, complexes I and IV are upregulated, and while ROS remains low, ATP levels are reinstated (orange arrows). The 6-chromanol SUL-138 mimics arousal mitochondria after daily torpor in mice by stimulating complex I and IV function, thereby reducing ROS levels and increasing ATP levels. SUL-138 affects complex IV function via the reduction of cytochrome c. In addition, SUL-138 changes metabolic input towards the oxidative phosphorylation system (OXPHOS) to fatty acid degradation and oxidation (FAD and FAO) (green arrows).

Figure 4

Proposed model for beneficial effects of hibernation-derived mitochondrial activation on synaptic plasticity. Alzheimer’s disease mitochondria have an imbalance in ROS/ATP, with excess ROS production and reduced ATP levels. This leads to pathological secondary outcomes, including inhibited local translation of synaptic plasticity proteins, which depends heavily on sufficient ATP supply. This local translation is important for synaptic maturation, which is essential for LTP and memory, both impaired in AD (red arrows). Mitochondrial reactivation during arousal after torpor offers a unique state in which ROS formation is inhibited and ATP production is reactivated. In daily torpor mice, this arousal phase is characterized by an increase in complex I and IV levels (orange arrows). SUL-138 mimics this reactivation of mitochondria by stimulating complex I and IV function, while preventing ROS formation (green arrows). Therefore, both torpor and torpor-derived mitochondrial activation by SUL-138 can lead to the enhanced local translation of synaptic plasticity proteins (e.g., AMPA/NMDA receptor subunits, auxiliary subunits, and neurofilaments), and hence, may lead to enhanced LTP and memory formation capacity.