SLC22A14 is a mitochondrial riboflavin transporter required for sperm oxidative phosphorylation and male fertility

Cell Rep. 2021 Apr 20;35(3):109025. doi: 10.1016/j.celrep.2021.109025.

Abstract

Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa mid-piece and show by genetic, biochemical, multi-omic, and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions. Specifically, we find that fatty acid β-oxidation (FAO) is defective with significantly reduced levels of acyl-carnitines and metabolites from the TCA cycle (the citric acid cycle) but accumulated triglycerides and free fatty acids in Slc22a14 knockout spermatozoa. We demonstrate that Slc22a14-mediated FAO is essential for spermatozoa energy generation and motility. Furthermore, sperm from wild-type mice treated with a riboflavin-deficient diet mimics those in Slc22a14 knockout mice, confirming that an altered riboflavin level causes spermatozoa morphological and bioenergetic defects. Beyond substantially advancing our understanding of spermatozoa energy metabolism, our study provides an attractive target for the development of male contraceptives.

Keywords: SLC22A14 transporter; energy metabolism; fatty acid β-oxidation; male infertility; riboflavin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Citric Acid Cycle / drug effects
  • Citric Acid Cycle / genetics*
  • Diet / methods
  • Fatty Acids / metabolism
  • Female
  • Fertility / genetics*
  • Fertilization in Vitro
  • Gene Expression
  • Humans
  • Infertility, Male / diet therapy
  • Infertility, Male / genetics*
  • Infertility, Male / metabolism
  • Infertility, Male / pathology
  • Male
  • Metabolome
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • Models, Molecular
  • Organic Cation Transport Proteins / chemistry
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism
  • Oxidative Phosphorylation / drug effects
  • Riboflavin / metabolism*
  • Riboflavin / pharmacology
  • Sperm Motility / drug effects
  • Sperm Motility / genetics
  • Spermatozoa / drug effects
  • Spermatozoa / metabolism*
  • Spermatozoa / pathology

Substances

  • Fatty Acids
  • Organic Cation Transport Proteins
  • SLC22A14 protein, human
  • Slc22a14 protein, mouse
  • acylcarnitine
  • Carnitine
  • Riboflavin