SIAH3 (siah E3 ubiquitin protein ligase family member 3) functions as a negative regulator of mitochondrial quality control and cellular metabolism. Unlike other SIAH family members, SIAH3 lacks ubiquitin ligase activity but plays crucial roles in mitochondrial homeostasis 1. The protein negatively regulates PINK1-mediated mitophagy by directly interacting with PINK1 and promoting its intra-mitochondrial aggregation, thereby preventing the elimination of dysfunctional mitochondria 1. SIAH3 is localized to mitochondria and interacts with proteins involved in mitochondrial ribosome biogenesis and translation 2. Functionally, SIAH3 shifts cellular metabolism from oxidative phosphorylation to glycolysis 2. The protein acts as a physiological mitophagy suppressor that facilitates axonal degeneration during development by forming complexes with parkin and preventing mitophagy activation 3. SIAH3 is frequently epigenetically silenced in various cancers, where it functions as a tumor suppressor 2. In disease contexts, SIAH3 is upregulated in Parkinson's disease brains and chr13 kidney disease, contributing to pathology through impaired mitochondrial clearance 14. Additionally, genetic variants in SIAH3 are associated with increased ventricular enlargement rates in neurodegenerative diseases 5.