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This study demonstrates that the peroxisomal protein PEX14 naturally localizes to mitochondria in human cells, challenging the previous assumption that mitochondrial PEX14 represents aberrant mislocalization. Using advanced microscopy techniques, researchers found that endogenous PEX14 resides on the mitochondrial outer membrane and that mitochondrial localization is essential for its function in creating new peroxisomes. Experiments with PEX14 variants showed that preventing mitochondrial access blocks peroxisome formation, while forcing PEX14 to mitochondria supports it, confirming mitochondria as a source of peroxisomal components.
Why it matters
These findings fundamentally revise our understanding of how peroxisomes form in cells, supporting the model that peroxisomes originate partly from mitochondria. This has important implications for understanding peroxisomal biogenesis disorders, a group of severe genetic diseases, and could inform development of therapeutic strategies targeting peroxisome dysfunction in metabolic and neurodegenerative conditions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Peroxisomes are essential for cellular homeostasis and human health due to their central metabolic and physiological functions. The peroxisomal membrane protein PEX14 is indispensable for matrix protein import into peroxisomes. Recent studies support a hybrid model in which pre-peroxisomal vesicles originating from both, mitochondria and the endoplasmic reticulum, fuse to generate peroxisomes. PEX14 has repeatedly been observed at mitochondria in biogenesis disease models or upon protein overexpression, but such localization has generally been interpreted as aberrant mislocalization. Whether endogenous PEX14 naturally localizes to mitochondria and contributes to peroxisome biogenesis has remained unknown. Here, using high-content and super-resolution microscopy, we demonstrate that endogenous PEX14 localizes to the mitochondrial outer membrane. We show that ectopically expressed PEX14 accumulates at mitochondria, and PEX14 variants unable to access mitochondria and restricted to peroxisomes fail to rescue the PEX14 knockout phenotype. Vice versa, a mitochondria-targeted PEX14 variant supports peroxisome biogenesis. Our results identify the physiological mitochondrial pool of PEX14 in human cells and establish it as an essential intermediate in de novo peroxisome biogenesis.