Mitotoxicity in distal symmetrical sensory peripheral neuropathies

Journal name:
Nature Reviews Neurology
Year published:
Published online


Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor—that is, intraepidermal nerve fibres—of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.

At a glance


  1. Clinical symptoms and biomarkers of chronic distal symmetrical sensory peripheral neuropathy.
    Figure 1: Clinical symptoms and biomarkers of chronic distal symmetrical sensory peripheral neuropathy.

    Patients with distal symmetrical sensory peripheral neuropathy due to cancer chemotherapeutic treatment, HIV and nucleoside analogue reverse transcriptase inhibitor therapy, or diabetes complain of similar sensory disturbances: numbness combined with a dysaesthetic sensation of pins-and-needles and/or burning pain, along with allodynia and hyperalgesia. These sensory abnormalities appear in both of the feet, or in both the feet and the hands. Skin punch biopsy often reveals a significant loss of sensory axons from the epidermis (intraepidermal nerve fibres), even in cases where electrodiagnostic studies are normal.

  2. Underlying mechanisms in the development of distal symmetrical sensory peripheral neuropathy.
    Figure 2: Underlying mechanisms in the development of distal symmetrical sensory peripheral neuropathy.

    Distal neuropathy does not result from degeneration of the somatosensory primary afferent neuron, as indicated by a lack of ATF3+ nuclear signalling (a marker of axonal injury) and preservation of peripheral nerve axons. Instead, both preclinical and clinical stages of distal neuropathy are associated with mitochondrial dysfunction that leads to IENF degeneration and emergence of spontaneous discharges. Abbreviations: IENF, intraepidermal nerve fibre; RNS, reactive nitrogen species; ROS, reactive oxygen species.

  3. Contribution of nitro-oxidative stress to mitochondrial dysfunction.
    Figure 3: Contribution of nitro-oxidative stress to mitochondrial dysfunction.

    During mitochondrial respiration, the oxidative phosphorylation pathway produces the proton gradient required for ATP production. Electrons leaking from the electron transport chain react with molecular oxygen to produce potentially damaging O2, which has the potential to generate other reactive oxygen species and—via interaction with NO—peroxynitrite. Under normal conditions, the antioxidant defence system (including MnSOD, catalase, glutathione and glutathione peroxidase) adequately reduces superoxide to water and molecular oxygen;81 however, if these mechanisms are overwhelmed, formation of peroxynitrite increases.89 In turn, peroxynitrite induces a bioenergetic deficit by disrupting the activities of metabolic enzymes, mitochondrial electron transport chain proteins, ATP synthase, and membrane transport proteins.80, 81 Notably peroxynitrite-induced damage to MnSOD creates a feed-forward mechanism for enhancing its own production, thus facilitating the hazardous accumulation of superoxide.80, 81 Blue lines indicate pathways for the formation of reactive oxygen and reactive nitrogen species, red lines indicate potential targets of peroxynitrite-induced mitochondrial dysfunction. Abbreviations: C, complex; MnSOD, manganese superoxide dismutase; NO, nitric oxide; O2, superoxide ion.

  4. Peroxynitrite decomposition catalysts.
    Figure 4: Peroxynitrite decomposition catalysts.

    These porphyrin-based agents, typified by MnTM-4-PyP5+, FeTM-4-PyP5+ and MnTE-2-PyP5+, act as dual MnSOD mimetics and peroxynitrite decomposition catalysts to eliminate peroxynitrite as well as potentially beneficial superoxide. The newer selective agents, SRI6 and SRI110, eliminate peroxynitrite while sparing superoxide. The charged metal centre of SRI6 is shielded by β-fused cyclohexenyl substituents, rendering it membrane-permeable and orally bioavailable.92 Moreover, the charged electron-withdrawing functionality of other agents such as FeTMPyP5+ is absent from SRI6, which reduces its MnSOD mimetic activity.92 SRI110 is also orally bioavailable owing to its electroneutrality.93 Through a two-electron reduction mechanism, SRI110 reacts with peroxynitrite to produce a manganese (V)–oxo intermediate with concomitant reduction of peroxynitrite to nitrite.93 The manganese (III) catalyst is then regenerated by endogenous reductants, completing a reductase-type cycle.93 Abbreviation: MnSOD, manganese superoxide dismutase.



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Author information
  1. Department of Anaesthesia, Faculty of Dentistry, and The Alan Edwards Centre for Research on Pain, McGill University, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada.
    • Gary J. Bennett
  2. Department of Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St Louis, MO 63104, USA.
    • Timothy Doyle &
    • Daniela Salvemini
ContributionsAll three authors provided substantial contributions to discussions of the content of the manuscript, researched the literature, and participated in writing, editing and revision of the manuscript.
Competing interests statementD.S. and the Saint Louis University School of Medicine have patents concerning the use of superoxide dismutase mimetics and peroxynitrite decomposition catalysts for the treatment and prevention of neuropathic pain (WO 2012033916 A1 20120315; US 20080318917 A1 20081225; WO 2005060437 A2 20050707; US 6214817 B1 20010410; WO 9858636 A1 19981230). G.J.B and T.D. declare no competing interests.
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  • Gary J. Bennett
    Gary Bennett is Professor and Canada Senior Research Chair in the Department of Anesthesia and the Faculty of Dentistry at McGill University, Montreal, QC, Canada and Adjunct Professor in the Department of Anesthesiology at the University of California, San Diego, CA, USA. He received his PhD in psychology from Virginia Commonwealth University in Richmond, VA, USA, and spent 20 years as a staff scientist at the Neurobiology and Anesthesiology Branch, National Institute of Dental Research, NIH, Bethesda, MD, USA). For the past 35 years his research has focused on neuropathic pain syndromes and the development of new analgesics.
    Contact Gary J. Bennett
  • Timothy Doyle
    Timothy Doyle is Research Assistant Professor in the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, MO, USA. He received his PhD from Saint Louis University for studying the inflammatory and biochemical mechanisms of septic shock, before his postdoctoral fellowship in the laboratory of Professor Daniela Salvemini researching the mechanisms underlying pain and pain therapeutics. His current research focuses on understanding the molecular, biochemical and inflammatory signaling pathways involved in the development and maintenance of chronic neuropathic pain.
  • Daniela Salvemini
    Daniela Salvemini is Professor in the Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, MO, USA. She received her BSc in pharmacology from King's College, London, UK and her PhD in pharmacology under the mentorship of Nobel Laureate Sir John R. Vane at the William Harvey Research Institute in London. She spent over a decade in the private sector, leading drug discovery efforts. Her research focuses on the cellular and molecular changes that underlie chronic pain and opioid-induced analgesic tolerance. Her research is highly translational and stresses cross-fertilization with discovery chemistry.