A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers

Abstract

The mechanisms of mitochondrial dysfunction in Alzheimer's disease are incompletely understood. Using two‐photon fluorescence lifetime microscopy of the coenzymes, NADH and NADPH, and tracking brain oxygen metabolism with multi‐parametric photoacoustic microscopy, we show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid‐β oligomers, which are precursors of amyloid plaques in Alzheimer's disease brain and stimulate mTORC1 protein kinase activity at the plasma membrane but not at lysosomes, block this Nutrient‐induced Mitochondrial Activity (NiMA) by a mechanism dependent on tau, which forms neurofibrillary tangles in Alzheimer's disease brain. NiMA was also disrupted in fibroblasts derived from two patients with tuberous sclerosis complex, a genetic disorder that causes dysregulation of lysosomal mTORC1. Thus, lysosomal mTORC1 couples nutrient availability to mitochondrial activity and links mitochondrial dysfunction to Alzheimer's disease by a mechanism dependent on the soluble building blocks of the poorly soluble plaques and tangles.

Are you TORC ing tau me? Amyloid‐β blocks the conversation between lysosomes and mitochondria

“…Many toxic effects of Aβos have been shown to be mediated through tau (Polanco et al , ). This also holds true for NiMA, as this process was not blocked by Aβos in tau knockout neurons (Norambuena et al , ). This reinforces the view that tau acts as a scaffolding protein, facilitating the formation of signalling complexes that affect neuronal function in several ways (Polanco et al , ).…”

“…Furthermore, the discovery of direct contact sites between lysosomes and mitochondria has sparked hypotheses of a potential cooperation between these two organelles under physiological conditions, as well as in the development of neurodegenerative diseases (Wong et al , ). In this issue, Norambuena et al () provide evidence that oligomeric forms of Aβ (Aβos) disrupt the functional crosstalk between lysosomes and mitochondria, thereby contributing to the early stages of AD.…”

“…Mitochondrial dysfunction impairs lysosomal structure and function in a manner that depends on the levels of mitochondrial reactive oxygen species (ROS; Demers‐Lamarche et al , ). Norambuena et al () demonstrate that there is also an opposite information flow, with mitochondria receiving signals from lysosomes via a mechanism that is dependent on mTORC1, a multiprotein signalling complex nucleated by mTOR and bound to the cytosolic side of lysosomes. This lysosome‐associated mTORC1 was shown to be activated by insulin and amino acids, leading to what the authors have termed “nutrient‐induced mitochondrial activation (NiMA)”, reflected by increased oxygen consumption and the mitochondrial production of ROS.…”

“…Work from our laboratory has shown that Aβos initiate a pathological cascade that results in the de novo synthesis of tau protein and its pathological phosphorylation; this occurs via activation of S6K1, albeit in an mTOR‐independent manner (Li & Götz, ). The new findings by Norambuena et al () potentially identify an early signature of AD, pointing at a convergence of various signalling pathways and presenting a reduction in mTOR activity as a valid therapeutic approach for the treatment of AD (Caccamo et al , ). Interestingly, suppression of mTOR has also been reported to increase health and lifespan in several organisms (Johnson et al , ), and it would not be surprising if in our journey to treat AD we also have a strong positive effect on its major risk factor, ageing.…”

“… How amyloid‐β (Aβ) and tau exacerbate Alzheimer's disease ( AD ) at a subcellular level is only incompletely understood. Norambuena et al () report crosstalk between mitochondria and lysosomes and identify a role for lysosomal mTORC 1 in the nutrient‐induced activation of mitochondria. This lysosomal signalling pathway is strongly inhibited by oligomeric Aβ through the tau‐dependent activation of plasma membrane‐localized mTORC 1.…”