# Cisd1 synergizes with Cisd2 to modulate protein processing by maintaining mitochondrial and ER homeostasis

## TL;DR

This study shows that Cisd1 and Cisd2 work together to maintain mitochondrial and ER balance, and their absence causes severe skeletal muscle defects and cellular dysfunction.

## Contribution

The study reveals a synergistic role of Cisd1 and Cisd2 in maintaining organelle homeostasis and protein processing in skeletal muscle.

## Key findings

- Cisd1 and Cisd2 deficiency causes mitochondrial degeneration, ER stress, and protein processing defects.
- Double knockout of Cisd1 and Cisd2 disrupts immune response, redox regulation, and metabolism.
- Cisd2 has a more critical role than Cisd1 in maintaining skeletal muscle function and organelle crosstalk.

## Abstract

Connection and crosstalk among the organelles critically contribute to cellular functions. Destruction of any kind of organelle is likely to induce a series of intracellular disorders and finally lead to cell death. Because of its subcellular locations, CDGSH iron-sulfur domain-containing protein 1 (Cisd1) and Cisd2 have functions that are related to maintaining mitochondria and ER homeostasis. As previous reports have shown, Cisd2 knockout mice have a decreased body weight and poor survival rate, and the primary defects were conducted in skeletal muscle. Our previous findings indicated that Cisd1 deletion causes a range of skeletal muscle defects in mice with Cisd2 deficiency, including mitochondrial degeneration, endoplasmic reticulum (ER) stress, and alteration of protein process, as well as programmed cell death. In Cisd1 and Cisd2 deficient condition, the whole of the protein biosynthesis was damaged, including translation, modification, transport, and degradation. Changes in the immune response, redox regulation, and metabolism were also present in Cisd1 and Cisd2 double knockout mice. Overall, we have demonstrated that Cisd1 and Cisd2 knockout have a synergistic effect on skeletal muscles, and that Cisd2 plays a more critical role than Cisd1. These synergistic effects impact signaling regulation and interrupt the crosstalk and homeostasis of organelles. This creates severe disorders in various tissues and organs.