Decreased membrane cholesterol in liver mitochondria of the point mutation mouse model of juvenile Niemann-Pick C1, Npc1nmf164

Mitochondrion. 2020 Mar;51:15-21. doi: 10.1016/j.mito.2019.12.003. Epub 2019 Dec 17.


It has long been known that there is decreased mitochondrial function in several tissues of Niemann-Pick C1 model mice and cultured cells. These defects contribute to the accumulation of Reactive Oxygen Species (ROS) and tissue damage. It is also well established that there is increased unesterified cholesterol, stored in late endosomes/lysosomes, in many tissues in mutant humans, mouse models, and mutant cultured cells. Using a mouse model with an NPC1 point mutation that is more typical of the most common form of the disease, and highly purified liver mitochondria, we find markedly decreased mitochondrial membrane cholesterol. This is compared to previous reports of increased mitochondrial membrane cholesterol. We also find that, although in wild-type or heterozygous mitochondria cytochrome c oxidase (COX) activity decreases with age as expected, surprisingly, COX activity in homozygous mutant mice improves with age. COX activity is less than half of wild-type amounts in young mutant mice but later reaches wild-type levels while total liver cholesterol is decreasing. Mutant mice also contain a decreased number of mitochondria that are morphologically abnormal. We suggest that the decreased mitochondrial membrane cholesterol is causative for the mitochondrial energy defects. In addition, we find that the mitochondrial stress regulator protein MNRR1 can stimulate NPC1 synthesis and is deficient in mutant mouse livers. Furthermore, the age curve of MNRR1 deficiency paralleled levels of total cholesterol. The role of such altered mitochondria in initiating the abnormal autophagy and neuroinflammation found in NPC1 mouse models is discussed.

Keywords: Cytochrome c oxidase; Liver; Mitochondria; Mitophagy; Niemann–Pick C1; Unesterified cholesterol.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Membrane / metabolism*
  • Cholesterol / analysis*
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Electron Transport Complex IV / metabolism
  • Female
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver / metabolism
  • Male
  • Mice
  • Mitochondria, Liver / metabolism*
  • Niemann-Pick C1 Protein
  • Niemann-Pick Disease, Type C / genetics*
  • Niemann-Pick Disease, Type C / pathology
  • Transcription Factors / metabolism*


  • Chchd2 protein, mouse
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Niemann-Pick C1 Protein
  • Npc1 protein, mouse
  • Transcription Factors
  • Cholesterol
  • Electron Transport Complex IV