Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Abstract

Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.

Ndufs4knockout induces transcriptomic signatures of Alzheimer’s Diseases that are partially reversed by mitochondrial complex I inhibitor

“…Interestingly, as is the case of complex I inhibitor metformin or complex I, III and V inhibitor resveratrol, continuous application of these compounds is safe 39,59 . Consistent with our previous findings in AD mice [37][38][39][40][41]43 , 3-day CP2 treatment in Ndufs4 -/males and females enhanced mitochondrial biogenesis, evident by increased mitochondrial translation and activation of transcription factors Tfeb and Tfam, which lead to the augmented expression of genes involved in the OXPHOS, the TCA cycle, and the mitochondria specific neuroprotective deacetylase Sirtuin 3 60 . Concomitantly increased mitochondrial biogenesis, translation and mitophagy indicate augmented mitochondrial turnover and replenishment.…”

“…The detailed investigation of the impact of Ndufs4 knockout on the assembly and stability of complex I revealed that other subunits or OXPHOS complexes, including Ndufaf2 and complex III, could function as stabilizing factors to explain a residual activity of complex I (~26% in isolated mitochondria) in the Ndufs4 -/mouse brain 30,54 . Extensive studies conducted to understand the mechanism of CP2 suggest that binding and mild inhibition of complex I is required to alter AMP/ATP ratio, activate AMPK and the subsequent signaling cascade [37][38][39][40][41]43 . Our studies in aging WT or symptomatic AD mice suggest that mild inhibition of complex I could be beneficial despite a presence of mitochondria with altered dynamics and function, similar to data generated with metformin 59,63 .…”

“…Previously, we identified the small molecule tricyclic pyrone compound CP2 as a mild mitochondrial complex I inhibitor [37][38][39][40][41][42][43] . Continuous CP2 treatment in multiple mouse models of AD, starting at in utero, pre-or symptomatic stages, reduced A and pTau accumulation, inflammation, oxidative damage, and improved brain and peripheral energy homeostasis.…”

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

“…Such a mitochondrial phenotype was later observed in the brains of OXYS rats, a model of sporadic AD [ 93 ], and in aged non-human primates [ 94 ]. Very recently, Panes and colleagues [ 95 ] reported that the MOAS morphology represented approximately 80% of the total mitochondria in the hippocampi of APP/PS1 mice. Moreover, they observed a significant interaction between MOAS and endoplasmic reticulum (ER) membranes, forming extensive mitochondria–ER contact sites (MERCS).…”

“…Moreover, they observed a significant interaction between MOAS and endoplasmic reticulum (ER) membranes, forming extensive mitochondria–ER contact sites (MERCS). Although the exact role of such an interaction remains unclear, the authors showed that reestablishing energy homeostasis reduced MOAS formation, MERCS coverage, and ER stress and enhanced the mitochondrial dynamics [ 95 ]. Alongside alterations in the CNS, previous studies refer to the existence of an abnormal mitochondrial distribution and morphology in fibroblasts from sporadic AD cases due to a reduction in Drp1 protein levels [ 96 ].…”