ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function

Area of Science:

• Cell Biology
• Molecular Biology
• Proteostasis

Background:

• Cellular proteostasis is essential for organism health.
• Protein synthesis is inherently error-prone, leading to misfolded proteins.
• Misfolded proteins can accumulate and cause cellular dysfunction.

Purpose of the Study:

• To investigate the cellular mechanisms for handling misfolded proteins originating from the endoplasmic reticulum (ER).
• To identify the pathways involved in the sequestration of ER-misfolded proteins into mitochondria.
• To characterize a novel mitochondria-associated proteostatic mechanism.

Main Methods:

• Cell fractionation and microscopy studies were employed.
• The role of the endoplasmic reticulum-mitochondria encounter structure (ERMES) was investigated.
• The impact of blocking ERMES on misfolded protein localization was assessed.

Main Results:

• Misfolded proteins from the ER can associate with and be partially transported into mitochondria.
• This sequestration impairs mitochondrial function.
• Blocking the ER-mitochondria encounter structure (ERMES) abrogated this sequestration process.
• The mitochondrial sorting and assembly machinery (SAM) and surveillance pathways (Msp1, Vms1) were not essential for this sequestration.
• A novel pathway, ER-associated mitochondrial sequestration (ERAMS), was identified.

Conclusions:

• ERAMS is a novel mitochondria-associated proteostatic mechanism for handling ER-misfolded proteins.
• ERAMS involves the ER-mitochondria encounter structure (ERMES).
• ERAMS dysfunction may contribute to pathological conditions involving misfolded proteins and mitochondrial dysfunction, as exemplified by mutant α-1-antitrypsin.