Rmdn3, also known as PTPIP51, is a protein that plays essential roles in multiple cellular processes. It is involved in the transport of phospholipids from the endoplasmic reticulum (ER) to mitochondria via the mitochondria-ER contact site (MERCS), maintaining mitochondrial function and integrity [1]. Rmdn3 also serves as a determinant of ER-mitochondria proximity in Purkinje cells [2]. Additionally, it is part of the VAPB-Rmdn3 tethers which regulate macroautophagy, and its phosphorylation may be involved in lipid radical transfer between ER and mitochondria to reduce mitochondrial oxidative stress [3,4].

In cell-type-specific profiling of brain mitochondria in MitoTag mice, Rmdn3 was identified as a determinant of ER-mitochondria proximity in Purkinje cells, suggesting its role in maintaining proper cellular functions in the central nervous system [2]. Disrupting the VAPB-Rmdn3 tethers by siRNA knockdown in cells stimulates autophagosome formation, indicating its significance in autophagy regulation [4]. Also, induction of mitochondrial ROS increases MERCs formation via Rmdn3-VAPB tethering driven by Rmdn3 phosphorylation, and disruption of this tethering leads to lipid radical accumulation in mitochondria and cell death, highlighting its role in cell survival under mitochondrial damage [3].

In conclusion, Rmdn3 is crucial for maintaining ER-mitochondria interactions, regulating autophagy, and reducing mitochondrial oxidative stress. Studies using mouse models and cell-based knockdown experiments have revealed its significance in these processes. Its potential implications in neurodegenerative diseases like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) suggest that understanding Rmdn3 may offer new therapeutic strategies for such age-related disorders [4,5,6].