Alzheimer’s disease (AD) is characterized by progressive metabolic failure, impaired mitochondrial function, and diminished adaptive stress responses, highlighting the need for disease-modifying therapies that restore cellular resilience rather than target downstream pathology. Here, we report the discovery and preclinical validation of C273, a translationally optimized, brain-penetrant mitochondrial complex I (mtCI) modulator developed through medicinal chemistry optimization of our first-generation compounds. C273 retained nanomolar neuroprotective activity against Aβ-induced toxicity while exhibiting favorable drug-like properties, including high oral bioavailability, efficient brain penetration, microsomal stability, minimal CYP and off-target pharmacology liabilities, and selective mild modulation of mtCI. Mechanistic studies demonstrated that C273 activated AMP-activated protein kinase (AMPK) and coordinated antioxidant, autophagic, anti-inflammatory, and mitochondrial quality-control pathways in cultured cells and mouse brain. These responses were absent in AMPKα1/α2-deficient cells, establishing AMPK as an essential mediator, while rotenone pretreatment abolished C273-mediated neuroprotection, supporting engagement of the mtCI quinone-binding site. Repeated administration to wild-type mice for 30 days produced no detectable cardiac or hepatic toxicity. Importantly, C273 activated the same neuroprotective pathways and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Together, these findings establish mild modulation of mtCI as a therapeutic strategy to restore metabolic resilience and identify C273 as a promising disease-modifying candidate for AD treatment.
Sergey Trushin, Thi Kim Oanh Nguyen, Mark Ostroot et al.· npj Drug Discovery· 0 citations
Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.
Ibrahim Shammas, Hazem Iaali, J. Watzlawik et al.· Brain : a journal of neurolo...· 0 citations
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