HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy.

Krystal English,Michelle Craig Barton

doi:10.3389/fnmol.2021.684714

Abstract

Peripheral neuropathy, which is the result of nerve damage from lesions or disease, continues to be a major health concern due to the common manifestation of neuropathic pain. Most investigations into the development of peripheral neuropathy focus on key players such as voltage-gated ion channels or glutamate receptors. However, emerging evidence points to mitochondrial dysfunction as a major player in the development of peripheral neuropathy and resulting neuropathic pain. Mitochondrial dysfunction in neuropathy includes altered mitochondrial transport, mitochondrial metabolism, as well as mitochondrial dynamics. The mechanisms that lead to mitochondrial dysfunction in peripheral neuropathy are poorly understood, however, the Class IIb histone deacetylase (HDAC6), may play an important role in the process. HDAC6 is a key regulator in multiple mechanisms of mitochondrial dynamics and may contribute to mitochondrial dysregulation in peripheral neuropathy. Accumulating evidence shows that HDAC6 inhibition is strongly associated with alleviating peripheral neuropathy and neuropathic pain, as well as mitochondrial dysfunction, in in vivo and in vitro models of peripheral neuropathy. Thus, HDAC6 inhibitors are being investigated as potential therapies for multiple peripheral neuropathic disorders. Here, we review emerging studies and integrate recent advances in understanding the unique connection between peripheral neuropathy and mitochondrial dysfunction through HDAC6-mediated interactions.

Highlights

Peripheral neuropathy is a chronic, debilitating disorder characterized by peripheral nerve damage occurring in multiple diseases such as diabetes, Charcot-Marie-Tooth disease, mitochondrial disease, and chemotherapy neurotoxicity (Colloca et al, 2017)
Though a deep discussion of non-neuronal histone deacetylase 6 (HDAC6) activity in mitochondrial function and dynamics is outside the scope of this review, these findings suggest multiple points of potential therapeutic intervention by HDAC6 inhibition in peripheral neuropathy
Histone deacetylase may be a missing link to fully understanding the role that mitochondria play in the development of peripheral neuropathy (Figure 1)

Summary

INTRODUCTION

Peripheral neuropathy is a chronic, debilitating disorder characterized by peripheral nerve damage occurring in multiple diseases such as diabetes, Charcot-Marie-Tooth disease, mitochondrial disease, and chemotherapy neurotoxicity (Colloca et al, 2017). There is little understanding of the underlying mechanisms that cause peripheral neuropathy and ineffective treatments for neuropathic pain. Though mitochondria are necessary for the health and survival of all cells, peripheral neurons are sensitive to homeostatic mitochondrial functions. Recent findings show that damage to mitochondria and aberrant mitochondrial transport in peripheral neurons are common features of peripheral neuropathy. Dysregulated HDAC6 correlates with peripheral neuropathy development, neuronal microtubule instability, and decreased axonal transport of mitochondria (Chen et al, 2010; Picci et al, 2020; Sakloth et al, 2020). Therapies targeting HDAC6 may restore balanced mitochondrial activity, mediate potential repair of peripheral neuropathy, and alleviate neuropathic pain (Adalbert et al, 2020). We discuss the emerging topic of HDAC6 activity and non-histone protein modifications linked to development of peripheral neuropathy by altered mitochondrial function and transport

PERIPHERAL NEUROPATHY AND NEUROPATHIC PAIN

HISTONE MODIFICATIONS ARE IMPORTANT FOR NEURONAL MICROTUBULE STABILITY

MITOCHONDRIAL TRANSPORT IS ALTERED IN MODELS OF PERIPHERAL NEUROPATHY

DISCUSSION