Symposium 1

Asst. Prof Lena Ho

Assistant Professor

Cardiovascular and Metabolic Disorders Programme

Duke-NUS Medical School

Dr. Lena Ho is an Assistant Professor of Cardiovascular and Metabolic Disorders at Duke-NUS Medical School. Dr. Ho received her PhD in Immunology from Stanford University and postdoctoral training in the Institute of Medical Biology (A*STAR). She established the Endogenous Peptides Lab at Duke-NUS in 2017 as a National Research Foundation Fellow and a Howard Hughes International Research Scholar.

Dr. Ho is internationally recognized for her work on small-open reading frame (sORF)-encoded small peptides. Her work has contributed to the understanding of how these peptides function in the endocrine and metabolic systems, there they function as secreted hormones and mitochondrial peptides, respectively.

Dr. Ho’s current research is focused on systematically defining the biological functions of sORF-encoded peptides, particularly those that participate in immune and metabolic regulation. Her team aims to target these peptides to improve metabolic disease, improve outcomes following microbial infection and alleviate chronic inflammation in various disease settings.

Session:

Building from the Bench (Model Systems to Understand Disease Mechanisms)
12 April 2024, 1045 - 1215, NAK Auditorium

Presenting Title:

Metabolic Regulation by Microproteins

Mitochondrial small-open reading frame encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Assembly of ETC complexes, in particular Complex I assembly, is a costly bioprocess that is tightly coupled to nutrient availability and redox status. Serine is a major source of 1-carbon units for anabolic growth and redox buffering, and its availability determines the levels of Complex I biogenesis. How mitochondria actively co-ordinate 1-carbon availability to Complex I levels is unknown. Using a genome-wide CRISPR screen against a comprehensive collection of SEPs, we find that a long non-coding RNA-encoded microprotein CRISTA is required for growth under oxidative conditions when the 1-carbon folate cycle is inhibited. CRISTA potentiates mitochondrial serine import via direct interactions with the serine transporter SFXN1 in the inner mitochondrial membrane. Its C-terminus furthermore interacts with the mitochondrial ribosome to form a SFXN1-CRISTA-mitoribosome triad that is enriched for mt-ND5 mRNA which encodes a core enzymatic and structural subunit of Complex I. Deletion of CRISTA reduces mitochondrial serine uptake, leading to reduced levels of folate intermediates. This in turn impairs 5-taurinomethyl(thio)uridinylation of mitochondrial tRNAs (tm5U and tm5s2U), leading to a specific loss of ND5 translation and a stall in Complex I biogenesis. Conversely, inhibition of the folate cycle destabilizes CRISTA, leading to an attenuation of Complex I assembly in response to reduced folate cycle metabolites. In mice, loss of CRISTA causes post-implantation lethality. Our work uncovers a novel and essential mechanism mediated by a microprotein that bridges 1-carbon flux to Complex I biogenesis, and establishes a prototypical example of localized mitochondrial translation controlled by metabolites through the physical apposition of mitoribosomes with metabolite transporters.

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