Design of diverse, functional mitochondrial targeting sequences across eukaryotic organisms using variational autoencoder

Boob, Aashutosh Girish; Tan, Shih-I; Zaidi, Airah; Singh, Nilmani; Xue, Xueyi; Zhou, Shuaizhen; Martin, Teresa A.; Chen, Li-Qing; Zhao, Huimin

doi:10.1038/s41467-025-59499-3

Title: Design of diverse, functional mitochondrial targeting sequences across eukaryotic organisms using variational autoencoder

Journal Article · Sun May 04 00:00:00 UTC 2025 · Nature Communications

DOI: https://doi.org/10.1038/s41467-025-59499-3 · OSTI ID:2564316

Boob, Aashutosh Girish ^[1]; Tan, Shih-I ^[1]; Zaidi, Airah ^[1];

^[1]; Xue, Xueyi ^[1]; Zhou, Shuaizhen ^[1]; Martin, Teresa A. ^[1];

^[1];

^[1]

University of Illinois Urbana-Champaign, IL (United States)

Mitochondria play a key role in energy production and metabolism, making them a promising target for metabolic engineering and disease treatment. However, despite the known influence of passenger proteins on localization efficiency, only a few protein-localization tags have been characterized for mitochondrial targeting. To address this limitation, we leverage a Variational Autoencoder to design novel mitochondrial targeting sequences. In silico analysis reveals that a high fraction of the generated peptides (90.14%) are functional and possess features important for mitochondrial targeting. We characterize artificial peptides in four eukaryotic organisms and, as a proof-of-concept, demonstrate their utility in increasing 3-hydroxypropionic acid titers through pathway compartmentalization and improving 5-aminolevulinate synthase delivery by 1.62-fold and 4.76-fold, respectively. Moreover, we employ latent space interpolation to shed light on the evolutionary origins of dual-targeting sequences. Overall, our work demonstrates the potential of generative artificial intelligence for both fundamental research and practical applications in mitochondrial biology.

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Research Organization:: University of Illinois Urbana-Champaign, IL (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0018420

OSTI ID:: 2564316

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 16; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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