Autophagy mediates phase transitions from cell death to life

Abstract

Autophagy is a lysosomal degradation pathway, which is critical for maintaining normal cellular functions. Despite considerable advances in defining the specific molecular mechanism governing the autophagy pathway during the last decades, we are still far from understanding the underlying principle of the autophagy machinery and its complex role in human disease. As an alternative attempt to reinvigorate the search for the principle of the autophagy pathway, we in this study make use of the computer-aided analysis, complementing current molecular-level studies of autophagy. Specifically, we propose a hypothesis that autophagy mediates cellular phase transitions and demonstrate that the autophagic phase transitions are essential to the maintenance of normal cellular functions and critical in the fate of a cell, i.e., cell death or survival. This study should provide valuable insight into how interactions of sub-cellular components such as genes and protein modules/complexes regulate autophagy and then impact on the dynamic behaviors of living cells as a whole, bridging the microscopic molecular-level studies and the macroscopic cellular-level and physiological approaches.

Computational modeling of the effects of autophagy on amyloid-β peptide levels

“…In this study we have investigated via modeling and simulations how autophagy activity affects Aβ kinetics such as the intra and extracellular levels, secretion, clearance, and autophagic degradation. The mathematical model has been extended from the multi-compartment autophagy model originally developed by Han and Choi [4,9,49,50] to the one with Aβ kinetics incorporated by accommodating the current working hypothesis [29][30][31] and the experimental mechanistic studies [28][29][30][31][32][33][34][35][36]51] on the relationship between autophagy activity and Aβ kinetics. Such multi-compartment frameworks [4,9,49,50] are especially useful for testing biological hypotheses regarding the selective autophagy including Aggrephagy (i.e., autophagic degradation of protein aggregates), Mitophagy (for mitochondria), and Xenophagy (for microbes) [54] because the model can be easily modified easily to incorporate new substrates for selective degradation in each compartment (see Fig.…”

“…with appropriate exponent δ h and constant k h for ATP, where r hi is the rate constant for intralysosomal hydrolysis [40,41]. Further details of the equations for autolysosome formation and intralysosomal hydrolysis can be found in literature [4,9,49,50].…”

“…with appropriate constant k s for amino acid, where C ðmÞ A is the ATP concentration corresponding to the maximal protein synthesis rate and r s denotes the rate constant for the protein synthesis. Further details of the protein synthesis can be found in literature [4,9,49,50].…”

“…Autophagy (from the Greek, autos, which means "self", and phagein, "to eat") is an evolutionarily conserved catabolic pathway, which delivers cytoplasmic constituents such as proteins and organelles to the lysosome for degradation and recycling [1][2][3]. Autophagy regulates protein quality, energy balance, and metabolic homeostasis, and furthermore it plays a role in the decision-making of cellular life and death, depending on the context of its activation [2][3][4][5]. The energy molecules and metabolic building blocks such as adenosine triphosphate (ATP) and amino acids, respectively, which are the recycled products of autophagy, regulate the consecutive steps of the autophagy process, i.e., sequestration (or autophagosome formation), autophagosome maturation (autolysosome formation), and intralysosomal hydrolysis, via mammalian target of rapamycin (mTOR) (for amino acids) and AMP-activated protein kinase (AMPK) pathways (for ATP) [6][7][8][9].…”

Insights into mortality patterns and causes of death through a process point of view model

“…In a similar manner autophagy, the process to remove damaged proteins and invasive pathogens in cells, is akin to vitality in that it declines with age by the accumulation of waste material. Analogous to vitality challenges, cells enter apoptosis when the rate of pathogen flux or protein damage exceeds the autophagic capacity (Cuervo et al 2005; Denton et al 2015; Han et al 2015). However, while these hallmarks have a mechanistic link to aging, individually they do not have strong correlations with measures of aging (e.g.…”