The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes

Am J Physiol Endocrinol Metab. 2019 Feb 1;316(2):E293-E304. doi: 10.1152/ajpendo.00394.2018. Epub 2018 Dec 4.

Abstract

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.

Keywords: MARCH5; PPARγ; adipose tissue; lipid metabolism; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism*
  • Adipogenesis
  • Adipose Tissue / metabolism*
  • Adult
  • Animals
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Obesity / metabolism*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Membrane Proteins
  • Mitochondrial Proteins
  • PPAR gamma
  • MARCHF5 protein, human
  • Marchf5 protein, mouse
  • Ubiquitin-Protein Ligases