Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease

Abstract

<jats:p> Autophagy has been strongly linked with hormesis, however, it is only relatively recently that the mechanistic basis underlying this association has begun to emerge. Lysosomal autophagy is a group of processes that degrade proteins, protein aggregates, membranes, organelles, segregated regions of cytoplasm, and even parts of the nucleus in eukaryotic cells. These degradative processes are evolutionarily very ancient and provide a survival capability for cells that are stressed or injured. Autophagy and autophagic dysfunction have been linked with many aspects of cell physiology and pathology in disease processes; and there is now intense interest in identifying various therapeutic strategies involving its regulation. The main regulatory pathway for augmented autophagy is the mechanistic target of rapamycin (mTOR) cell signaling, although other pathways can be involved, such as 5′-adenosine monophosphate-activated protein kinase. Mechanistic target of rapamycin is a key player in the many highly interconnected intracellular signaling pathways and is responsible for the control of cell growth among other processes. Inhibition of mTOR (specifically dephosphorylation of mTOR complex 1) triggers augmented autophagy and the search is on the find inhibitors that can induce hormetic responses that may be suitable for treating many diseases, including many cancers, type 2 diabetes, and age-related neurodegenerative conditions. </jats:p>

Diabetes Mellitus and Periodontitis Share Intracellular Disorders as the Main Meeting Point

“…Recent evidence has shown that mitochondrial hormesis plays a role in the restoration of mitochondrial function and superoxide production via activation of the AMPK pathway. This mechanism has been related to the improvement of molecular markers of diabetes complications [30,106,107]. Recent evidence has shown that mitochondrial hormesis plays a role in the restoration of mitochondrial function and superoxide production via activation of the AMPK pathway.…”

“…Recent evidence has shown that mitochondrial hormesis plays a role in the restoration of mitochondrial function and superoxide production via activation of the AMPK pathway. This mechanism has been related to the improvement of molecular markers of diabetes complications [30,106,107].…”

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

“…That sclerostin protein abundance is post-translationally controlled may have important implications in age-related osteoporosis and the reduced sensitivity of osteocytes to mechanical cues with aging ( Hemmatian et al, 2017 ; Haffner-Luntzer et al, 2016 ). Lysosome activity is diminished with age ( Moore, 2020 ; Stead et al, 2019 ), including in the osteocyte during age-related bone loss ( Chen et al, 2014 ), an effect that could impair sclerostin degradation and new bone formation even in the face of osteoanabolic signals. While undoubtedly multifaceted in its impacts, targeting autophagy and lysosome activity to improve bone mass in aging has been proposed ( Li et al, 2020 ; Wang et al, 2019 ), and these data suggest that impacts on sclerostin bioavailability might contribute mechanistically to its efficacy.…”

Aging affects cognition and hippocampal ultrastructure in male Wistar rats

“…As a result, cellular control mechanisms stimulate mitophagy to remove damaged mitochondria via lysosomes (Bakula & Scheibye‐Knudsen, 2020; Chen et al., 2020; Jang et al., 2018). This results in an increased number of lysosomes containing nondegraded molecules, which lowers the turnover of functional mitochondria leading to enhanced oxidative stress, lower energy production, and catabolic dysfunction (Carmona‐Gutierrez et al., 2016; Moore, 2020; Q. Wang & Zennadi, 2020). Because pro‐apoptotic proteins do not degrade effectively, the increased concentrations of lipofuscin are often associated with increased apoptosis (Gray & Woulfe, 2005; Ng'oma et al., 2014).…”