Proteasome dysfunction induces excessive proteome instability and loss of mitostasis that can be mitigated by enhancing mitochondrial fusion or autophagy

摘要: The ubiquitin-proteasome pathway (UPP) is central to proteostasis network (PN) functionality and proteome quality control. Yet, the functional implication of UPP in tissue homeodynamics at whole organism level its potential cross-talk with other proteostatic or mitostatic modules are not well understood. We show here that knock down (KD) proteasome subunits Drosophila flies, induced, for most subunits, developmental lethality. Ubiquitous specific dysfunction triggered systemic instability activation PN modules, including macroautophagy/autophagy, molecular chaperones antioxidant cncC (the fly ortholog NFE2L2/Nrf2) pathway. Also, KD increased genomic instability, altered metabolic pathways severely disrupted mitochondrial functionality, triggering a cncC-dependent upregulation genes enhanced rates mitophagy. Whereas, overexpression key regulators responses (e.g., foxo) could suppress deleterious effects dysfunction; these were alleviated both larvae adult flies by modulating dynamics towards fusion enhancing autophagy. Our findings reveal extensive wiring genomic, higher metazoans. they support notion age-related increase proteotoxic stress due decreased activity deregulates all aspects cellular being thus driving force diseases. Abbreviations: ALP: autophagy-lysosome pathway; ARE: response element; Atg8a: autophagy-related 8a; ATPsynβ: ATP synthase, β subunit; C-L: caspase-like proteasomal activity; cncC: cap-n-collar isoform-C; CT-L: chymotrypsin-like Drp1: dynamin related protein 1; ER: endoplasmic reticulum; foxo: forkhead box, sub-group O; GLU: glucose; GFP: green fluorescent protein; GLY: glycogen; Hsf: heat shock factor; Hsp: Heat Keap1: kelch-like ECH-associated Marf: assembly regulatory NFE2L2/Nrf2: nuclear factor, erythroid 2 like 2; Opa1: optic atrophy PN: network; RNAi: RNA interference; ROS: reactive oxygen species; ref(2)P: refractory sigma P; SQSTM1: sequestosome SdhA: succinate dehydrogenase, subunit A; T-L: trypsin-like TREH: trehalose; UAS: upstream sequence; Ub: ubiquitin; UPR: unfolded response; UPP: