Figure 3:

Autophagy regulatory mechanisms in response to various cardiorenal metabolic stimuli (e.g., overnutrition/obesity, hyperlipidemia, insulin resistance, diabetes mellitus, inflammation and hypertension). The PI3K-Akt and AMPK signaling cascades represent the two major cell signaling pathways in response to cardiorenal metabolic stress. Typically, mTOR (with PI3K-Akt being the upstream activator) suppresses autophagy through inhibition of the ULK1 complex (ULK1-ATG13-FIP200) that is required for autophagy induction. AMPK activates the ULK1 complex or indirectly suppress mTOR to initiate autophagy. ROS directly or indirectly (through ER stress) turns on autophagy. The mTOR- independent autophagy regulating autophagy are less clear. One example is c-Jun N-terminal kinase (JNK)-regulated phosphphorylation (or inhibition) of Bcl-2, leading to relieve of Bcl-2-Beclin 1 coupling and its inhibition on autophagy induction. The ULK1 complex consisting of ATG1 (ULK1)-ATG13 and ATG17 recruits Vps34, Beclin-1, and Vpsl5 for autophagosome synthesis, possibly through mTOR-independent pathway(s). Two ubiquitin-like conjugation systems involving ATGs govern the elongation of phagophores. The ATG5-ATG12 conjugation involves ATG7 (El-like) and ATG10 (E2-like), whereas the light chain 3 (LC3, also commonly known as ATG8)-LC3-I- phosphatidylethanolamine (PE) conjugation involves ATG4 (a cysteine protease), ATG7 (El-like), and ATG3 (E2-like). The ATG5-ATG12 conjugate generates a complex with ATG16 to control LC3-I-PE conjugation (resulting in LC3-II). Arrowheads and “T” ended line lines represent activation and inhibition, respectively. AMPK, AMP-activated protein kinase; Akt: also known as Protein Kinase B (PKB); mTOR, mammalian target of rapamycin; Rheb, Ras homology enriched in brain; TSC, tuberous sclerosis complex. Part of this cartoon is modified from (Y. Zhang, et al., 2018).