The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.

Highlights d Longer forms of respiratory chain proteins accumulate under mitochondrial stress d Such proteins are formed by co-translational C-terminal extension (MISTERMINATE) d Such proteins can impair respiratory chain and also form cytosolic aggregates d MISTERMINATE links mitochondrial dysfunction with proteostasis failure in disease

Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing–like activity in metazoans remain unclear. Here we show that CAT–tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated GGGGCC (G4C2) repeat expansion in C9ORF72, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to be cotranslationally imported into mitochondria. However, poly(GR) translation on mitochondrial surface is frequently stalled, triggering RQC and CAT-tailing–like C-terminal extension (CTE). CTE promotes poly(GR) stabilization, aggregation, and toxicity. Our genetic studies in Drosophila uncovered an important role of the mitochondrial protease YME1L in clearing poly(GR), revealing mitochondria as major sites of poly(GR) metabolism. Moreover, the mitochondria-associated noncanonical Notch signaling pathway impinges on the RQC machinery to restrain poly(GR) accumulation, at least in part through the AKT/VCP axis. The conserved actions of YME1L and noncanonical Notch signaling in animal models and patient cells support their fundamental involvement in ALS/FTD.

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Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here we describe a phenomenon termed MISTERMINATE (mitochondrial stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs including complex-I 30kD subunit (C-I30) mRNA, occurring on mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C-terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally-extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE. translation, attenuated disease progression (Johnson et al., 2013). These studies strongly support an intimate connection between mitochondria and cytosolic translation, although the underlying mechanism is poorly defined.Here we provide a molecular link between mitochondrial function and cytosolic translation/proteostatsis. Mitochondrial damage induces translational stalling of mitochondrial outer membrane (MOM)-associated C-I30 mRNA by impairing the termination and ribosomerecycling factors eRF1 and ABCE1. Stalled ribosomes continue to add certain AAs to the Cterminus of C-I30, in a process analogous to CAT-tailing but with distinct features. C-I30 with C-terminal extension (CTE) inhibits oxidative phosphorylation (OxPhos) when assembled into C-I, and disrupts proteostasis when aggregating in the cytosol. Genetic manipulations of eRF1, ABCE1, or conserved CAT-tailing machinery prevent C-I30 CTE formation and rescue neuromuscular degeneration in PINK1 flies. PINK1/Parkin mechanistically regulates the RQC and CTE processes. These results identify C-I30 and possibly ATP5a as the first endogenous metazoan substrates of the CTE process, revealing intimate connections between mitochondrial health, co-translational QC, and proteostasis in neuromuscular tissues. RESULTS A Novel Form of C-I30 in PINK1 Neuromuscular TissuesHuman C-I is the largest enzyme of the respiratory chain, comprising 45 nuclear-or mitochondrial-encoded subunits, with C-I30 being part of the core assembly (Formosa et al., 2018). Mutations in C-I30 cause OxPhos and neuromuscular defects in Leigh syndrome. C-I30mRNA is translationally repressed in the cytosol before being recruited to MOM and reactivated by PINK1 and Parkin (Gehrke et al., 2015), two factors linked to familial PD.In muscle and brain tissues of PINK1 flies, we detected canonical C-I30...