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First published online 13 October 2009
doi: 10.1242/jcs.051862

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Keratins modulate the shape and function of hepatocyte mitochondria: a mechanism for protection from apoptosis

¹ Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-5622, USA
² Department of Surgery, Stanford University, Palo Alto, CA 94305, USA
³ Department of Medicine, Stanford University, Palo Alto, CA 94305, USA
⁴ Department of Biology, Abo Akademi University, 20521 Turku, Finland
⁵ Department of Internal Medicine I, University of Ulm, 89081 Ulm, Germany
⁶ State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China

^* Author for correspondence (mbishr{at}umich.edu)

Accepted 25 August 2009

Summary

Absence or mutation of keratins 8 (K8) or 18 (K18) cause predisposition to liver injury and apoptosis. We assessed the mechanisms of hepatocyte keratin-mediated cytoprotection by comparing the protein expression profiles of livers from wild-type and K8-null mice using two-dimensional differential-in-gel-electrophoresis (2D-DIGE) and mass spectrometry. Prominent among the alterations were those of mitochondrial proteins, which were confirmed using 2D-DIGE of purified mitochondria. Ultrastructural analysis showed that mitochondria of livers that lack or have disrupted keratins are significantly smaller than mitochondria of wild-type livers. Immunofluorescence staining showed irregular distribution of mitochondria in keratin-absent or keratin-mutant livers. K8-null livers have decreased ATP content; and K8-null mitochondria have less cytochrome c, increased release of cytochrome c after exposure to Ca²⁺ and oxidative stimulation, and a higher sensitivity to Ca²⁺-induced permeability transition. Therefore, keratins play a direct or indirect role in regulating the shape and function of mitochondria. The effects of keratin mutation on mitochondria are likely to contribute to hepatocyte predisposition to apoptosis and oxidative injury, and to play a pathogenic role in keratin-mutation-related human liver disease.

Key words: Intermediate filaments, Keratin 8, Keratin 18, Cytoprotection, Mitochondria, Liver injury, Apoptosis, Cytochrome c release, Oxidative stress

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