Lipid News

Lipid regulation of mitochondria

Yoshihiro Adachi Miho Iijima Hiromi Sesaki
By Yoshihiro Adachi, Miho Iijima and Hiromi Sesaki
May 01, 2019

Mitochondria are dynamic organelles that grow, divide and fuse in most of the human body’s cells; these dynamic membrane processes are critical for mitochondrial health.

Our laboratory studies mitochondrial division and fusion, focusing on three mechanochemical dynamin-related GTPases: Drp1, mitofusin and Opa1. Drp1 is a soluble GTPase that splits the mitochondrial membrane. Mitofusin and Opa1 are integral membrane GTPases that work together to fuse the mitochondrial membranes. Mutations in each of these enzymes lead to human diseases that mainly affect central and peripheral nervous systems.

Mitochondrial division and fusion need to be balanced to maintain functional mitochondrial size, structure and distribution within cells. This dynamic balance is controlled by several layers of mechanisms, including gene expression, post-translational modifications and protein degradation of these GTPases and their binding partners. In addition, mitochondrial phospholipids play important roles in regulation of mitochondrial dynamics.

CardiolipinCardiolipin, or CL, in the mitochondrial outer membrane promotes oligomerization of Drp1 to drive mitochondrial division; CL in the inner membrane mediates fusion through heterotypic interactions with Opa1. Hiromi Sesaki et al.Drp1 interacts with two phospholipids, cardiolipin, or CL, and phosphatidic acid, or PA, in the mitochondrial outer membrane, or OM. CL is synthesized in the mitochondrial inner membrane, or IM, and a fraction of CL is transported to the OM. Drp1 is recruited to the mitochondria through its receptor proteins on the surface of mitochondria; binding to CL stimulates Drp1 to assemble into high-order oligomers that function as a division machinery. The machinery is regulated further by PA. Binding to PA restrains the assembled machinery from initiating the constriction of the mitochondrial membranes, likely creating a priming step for mitochondrial division. Binding sites for CL and PA are different in Drp1; therefore, these phospholipids may create different degrees of the regulation through a combination of single or concurrent binding to Drp1.

The production of CL and PA is a dynamic process in the OM. As described above, CL is transported to the OM from the IM. This transport may be regulated through dynamic interactions at the intramitochondrial OM-IM contact sites. In the OM, there is a phospholipase D, MitoPLD, which converts CL to PA. Since MitoPLD directly binds Drp1, conversion of stimulatory CL to inhibitory PA may happen locally in the vicinity of the division machinery. PA also is produced in the endoplasmic reticulum, or ER, and imported into the OM through ER-mitochondrial contact sites. Drp1 often divides mitochondria at these sites. Mitochondrial PA levels also may be regulated by this interorganellar interaction.

PA changes the mitochondrial membrane’s biophysical properties and facilitates mitofusion-mediated membrane fusion. Opa1, similar to Drp1, binds CL, and this interaction drives membrane fusion. Therefore, lipid transport and synthesis coupled to intramitochondrial contact site dynamics and interorganellar interactions play key roles in controlling mitochondrial dynamics.

Yoshihiro Adachi
Yoshihiro Adachi

Yoshihiro Adachi is a postdoctoral fellow in Hiromi Sesaki’s lab in the department of cell biology at the Johns Hopkins University School of Medicine.

Miho Iijima
Miho Iijima

Miho Iijima is an associate professor in the department of cell biology at the Johns Hopkins University School of Medicine.

Hiromi Sesaki
Hiromi Sesaki

Hiromi Sesaki is a professor in the department of cell biology at the Johns Hopkins University School of Medicine.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Why you need more vitamin D in the winter
Wellness

Why you need more vitamin D
in the winter

January 26, 2020

With less exposure to sunlight in winter, adults should take in at least 600 international units per day of vitamin D from supplements or foods like oily fish, mushrooms and fortified dairy.

From the journals: MCP
Journal News

From the journals: MCP

January 25, 2020

Read about capturing a peptide link between migraines and opioid-induced sensitivity, profiling autologous body fluid exosomes and finding the RSK in melanoma protein interactions.

From the journals: JBC
Journal News

From the journals: JBC

January 24, 2020

Recent topics include misfolded tau proteins in Alzheimer’s disease, how enzymes trim peptides and how a parasite hijacks the immunity of its host.

Early immune response may improve cancer immunotherapies
Journal News

Early immune response may improve cancer immunotherapies

January 23, 2020

University of Illinois at Chicago researchers and colleagues report a new mechanism for detecting foreign material during early immune responses.

Do sperm offer the uterus a secret handshake?
Journal News

Do sperm offer the uterus
a secret handshake?

January 22, 2020

Why does it take 200 million sperm to fertilize a single egg? A female immune response is one reason. A molecular handshake may help sperm survive the bombardment.

A new hotspot for cyclooxygenase inhibition
Lipid News

A new hotspot
for cyclooxygenase inhibition

January 21, 2020

Drugs like aspirin dampen inflammation by inhibiting certain enzymes but can have nasty gastrointestinal side effects, so enzymologists are investigating the structure of the enzymes’ active sites in hopes of designing more selective inhibitors.