Preprint Watch 2026-06-07: 1 Clinical Failures Flagged for SOD1 | Claidex

Claidex Preprint Watch

doi:10.64898/2026.06.03.729791

Preprint WatchModerateJune 7th, 2026

Uncovering moonlighting role of mitochondrial presequence translocase machinery in SOD1-mediated ALS pathogenesis

Waingankar, T. P.; Paliwal, A.; Deep, A.; D'Silva, P.

The mitochondrial presequence translocase machinery has a moonlighting role in SOD1 mutant-mediated ALS pathogenesis through impaired organellar protein import.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Claidex indexed an efficacy failure on the SOD1 axis, the Phase 3 futility of oral edaravone (MT-1186) in ALS (mt-1186-oral-edaravone-sod1-als-phase3-futility). This preprint locates SOD1 toxicity in mitochondrial protein import via the presequence translocase rather than in bulk oxidative stress. That mechanism aligns with the indexed efficacy failure by suggesting an antioxidant scavenging strategy addressed a downstream consequence rather than the driver, and it points to a different intervention node. The convergence on an efficacy-relevant mechanism raises the signal to MODERATE.

Abstract excerpt

Familial Amyotrophic Lateral Sclerosis (fALS) is a fatal neurodegenerative disease, mainly caused by mutations in the superoxide dismutase 1 (SOD1) protein. Mitochondrial dysfunction is a primary hallmark of ALS pathogenesis. However, the molecular mechanism by which SOD1 mutants impair organellar health remains enigmatic. This study demonstrates that mutant SOD1 associates with the TIM23 complex in Saccharomyces cerevisiae via its intermembrane space (IMS) domain. In ALS-associated SOD1 mutants, both binding and expression of TIM23 complex proteins were downregulated, leading to altered translocation of the substrate protein Sdh3, a component of the electron transport chain (ETC) complex II. Disrupted Sdh3 translocation leads to mitochondrial dysfunction, evidenced by decreased ETC complex II activity, reduced functional mass, and compromised organelle integrity. Overexpression of Tim23 partially rescued mitochondrial integrity by increasing ETC complex activity and functional mass and restoring reticular morphology. Strikingly, the improved mitochondrial homeostasis in Tim23-overexpressing cells partially rescued the growth defects caused by mutant SOD1. Collectively, these findings reveal a previously unrecognized regulatory axis between mutant SOD1 and the mitochondrial pre-sequence translocase machinery, highlighting this pathway as a promising target for future ALS therapies and opening new avenues for mechanistic and translational research.

Matching Claidex post-mortems

1 of 1 indexed

May 23, 2026MT-1186 oral edaravone in ALS: a Phase 3b extension follows its parent into futilityMT-1186 (oral edaravone)EfficacyMRS 33

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.