What question did this study set out to answer?

Explore how LonP1 interacts with its native substrate to understand its role in mitochondrial function.

March 18, 2026Open Access

Structural Analysis of Human LonP1 Protease Bound with the Native Substrate

MLMing LiUniversity of Science and Technology of China HLHongwei LiuUniversity of Science and Technology of China SZShengchun ZhangSouth China Normal University

Key Points

Explore how LonP1 interacts with its native substrate to understand its role in mitochondrial function.
High-resolution cryo-electron microscopy (cryo-EM)
Analysis of human LonP1 hexamer structure
Investigation of substrate binding mechanisms
Reconstruction of high-resolution structure of LonP1 engaging substrate TFAM
Identification of a bipartite search-and-shred mechanism
Observation of a compact N-terminal domain that acts as a selective vestibule
Elucidation of a hand-over-hand threading mechanism through the central channel

Abstract

The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native physiological substrates remains elusive. Here, we present the high-resolution cryo-EM structure of the human LonP1 hexamer actively engaging its native substrate, TFAM. The reconstruction reveals a distinct bipartite search-and-shred mechanism. Unlike its bacterial homologs, the human N-terminal domain (NTD) adopts a compact architecture acting as a selective vestibule to recruit and initially unfold the substrate tertiary structure. Subsequently, the polypeptide is threaded through the central channel via a hand-over-hand mechanism driven by a spiral array of aromatic pore-loops. This structural framework provides a mechanistic rationale for the spatial segregation of LonP1 and offers a template for targeting mitochondrial proteostasis in human diseases.

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