Kidney epithelial targeted mitochondrial transcription factor A deficiency results in progressive mitochondrial depletion associated with severe cystic disease

Ken Ishii, Hanako Kobayashi, Kensei Taguchi, Nan Guan, Andraia Li, Carmen Tong, Olena Davidoff, Pamela V. Tran, Madhulika Sharma, Navdeep S. Chandel, Meghan E. Kapp, Agnes B. Fogo, Craig R. Brooks, Volker H. Haase*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells. TFAM deficiency resulted in significantly decreased mitochondrial gene expression, mitochondrial depletion, inhibition of nephron maturation and the development of severe postnatal cystic disease, which resulted in premature death. This was associated with abnormal mitochondrial morphology, a reduction in oxygen consumption and increased glycolytic flux. Furthermore, we found that TFAM expression was reduced in murine and human polycystic kidneys, which was accompanied by mitochondrial depletion. Thus, our data suggest that dysregulation of TFAM expression and mitochondrial depletion are molecular features of kidney cystic disease that may contribute to its pathogenesis.

Original languageEnglish (US)
Pages (from-to)657-670
Number of pages14
JournalKidney international
Volume99
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • TFAM
  • glycolysis
  • kidney development
  • mitochondria
  • polycystic kidney disease

ASJC Scopus subject areas

  • Nephrology

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