Mitochondrial Dysfunction and Therapeutic Targets in Auditory Neuropathy

Abstract

Sensorineural hearing loss (SNHL) becomes an inevitable worldwide public health issue, and deafness treatment is urgently imperative; yet their current curative therapy is limited. Auditory neuropathies (AN) were proved to play a substantial role in SNHL recently, and spiral ganglion neuron (SGN) dysfunction is a dominant pathogenesis of AN. Auditory pathway is a high energy consumption system, and SGNs required sufficient mitochondria. Mitochondria are known treatment target of SNHL, but mitochondrion mechanism and pathology in SGNs are not valued. Mitochondrial dysfunction and pharmacological therapy were studied in neurodegeneration, providing new insights in mitochondrion-targeted treatment of AN. In this review, we summarized mitochondrial biological functions related to SGNs and discussed interaction between mitochondrial dysfunction and AN, as well as existing mitochondrion treatment for SNHL. Pharmaceutical exploration to protect mitochondrion dysfunction is a feasible and effective therapeutics for AN.

Figure 1

Mitochondrial dysfunction mechanism of spiral ganglion neurons in auditory neuropathy. Although mechanisms of mitochondrial dysfunction have not been illustrated distinctly, damages in following targets have been mentioned: (1) mitochondrial homeostasis including biogenesis, dynamics, and mitophagy; (2) redox homeostasis and energetic metabolism; (3) mitochondrial calcium homeostasis; and (4) proapoptotic signal in mitochondria. Drp1: dynamin-related protein 1; MFN1/2: mitofusin 1/2; OPA1: optic atrophy 1; PGC1-α: peroxisome proliferator-activated receptor γ coactivator-1 α; TFAM: mitochondrial transcription factor A; TCA: tricarboxylic acid; ETC: electron transport chain; MCU: mitochondrial calcium uniporter; VDAC: voltage-dependent anion channel; NCLX: Na+/Ca2+/Li+ exchanger; Bcl-2: B cell lymphoma-2; BAX: Bcl-2 associated protein X; AIF: apoptosis inducing factor.

Figure 2

Pharmacological targets of mitochondria in auditory neuropathy. Pharmacological therapeutics of mitochondrial dysfunction to rescue auditory neuropathies are still limited. Proven therapeutic strategy targets are comprised of apoptosis inhibition, sirtuin mediators maintaining mitochondrial homeostasis and capability of metabolism, and antioxidants and free radical scavengers that are helpful to alleviate oxidative stress.