Mitochondria Bound to Lipid Droplets: Where Mitochondrial Dynamics Regulate Lipid Storage and Utilization

Abstract

The isolation and biochemical characterization of lipid droplet (LD)-associated mitochondria revealed the capacity of the cell to produce and maintain distinct mitochondrial populations carrying disparate proteome and dissimilar capacities to oxidize fatty acids and pyruvate. With mitochondrial motility being a central parameter determining mitochondrial fusion, adherence to LDs provides a mechanism by which peridroplet mitochondria (PDM) remain segregated from cytoplasmic mitochondria (CM). The existence of metabolically distinct subpopulations provides an explanation for the capacity of mitochondria within the individual cell to be involved simultaneously in fatty acid oxidation and LD formation. The mechanisms that deploy mitochondria to the LD and the dysfunctions that result from unbalanced proportions of PDM and CM remain to be explored. Understanding the roles and regulation of mitochondrial tethering to LDs offers new points of intervention in metabolic diseases.

Keywords: adipose tissue; fat; fatty acid oxidation; lipid; lipid droplet; mitochondria; obesity; peridroplet mitochondria; triacylglyceride; triacylglycerol.

Figure 1.

Images of peridroplet mitochondria. A. Living cultured brown adipocytes with lipid droplets stained with BODIPY (green) and mitochondria stained with MitoTracker Red (red). White line denotes peridroplet mitochondria. B. Electron micrograph of brown adipose tissue demonstrating mitochondria (red line) associated with a lipid droplet (LD). C. Isolated brown adipose tissue lipid droplets stained with BODIPY and MitoTracker Red, note the adherence of mitochondrial particles to lipid droplets. D. Living cultured INS-1 insulinoma cells over-expressing the lipid coating protein Plin5, which recruits mitochondria to lipid surface, stained with DAPI, BODIPY, and MitoTracker. Cell boarder marked by white line.

Figure 2.

Scheme of metabolic specialization model of CM and PDM. Metabolic specialization in PDM and CM: Mitochondria support lipogenesis with malonyl-CoA, a metabolite that inhibits FA oxidation by the mitochondria. Separation of mitochondria into PDM and CM may allow for both fatty acid oxidation and lipid synthesis to occur in the same cell at the same time. High pyruvate oxidation capacity in PDM may lead to increased malonyl-CoA pools. Malonyl-CoA can act as a negative regulator of Carnitine palmitoyltransferase I (CPT1) and thereby block fatty acid entry into mitochondria. In addition, malonyl-CoA is a building block for de novo lipid synthesis. Higher ATP synthesis capacity in PDM supports fatty acid esterification into triacylglycerides for lipid droplet expansion. Lower pyruvate oxidation in CM leads to reduced citrate and malonyl-CoA pools, which allow CPT1 to import fatty acids for β-oxidation (β-Ox). Increased β-oxidation products inhibit PDH and several steps of the tricarboxylic acid (TCA) cycle (for details see Figure S1). ETC: Electron transport system, ACC: acetyl-CoA carboxylase.